Triazoles for the treatment of demyelinating diseases

ABSTRACT

The invention relates to triazole compounds of formula I and I′ or pharmaceutically acceptable salts thereof, useful as modulators of demyelinating diseases: 
     
       
         
         
             
             
         
       
     
     The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, methods of using the compositions and kits thereof in the treatment of various demyelinating and neurodegenerative diseases, including multiple sclerosis.

RELATED APPLICATIONS

This application claims the benefit of the filing date under 35 U.S.C. §119(e) of Provisional U.S. Patent Application Ser. No. 62/171,784, filed Jun. 5, 2015, and Provisional U.S. Patent Application Ser. No. 62/326,471, filed Apr. 22, 2016, and which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system, characterized by myelin loss and degeneration of axons (see, Blakemore, et al., J. of Neuroimmunology, 98, 69-76, 1999). Activation and CNS infiltration of the peripheral immune system is typical in early stages of the disease, but can become less prevalent as disease progresses.

A hallmark of MS is loss of myelin, accompanied by the death of associated oligodendrocytes (see, Merrill, J. E. et al., Neuropathology and Applied Neurobiology, 25, 435-458, 1999). Myelin, which is produced by oligodendrocytes, ensheathes axons and dramatically increases conduction velocity of neural impulses while providing trophic support to the neuron. Myelin is thought to regenerate early in disease, as oligodendroycte progenitor cells (OPCs) proliferate and generate new myelinating oligodendrocytes in response to demyelination events. As the disease progresses the regenerative capacity of the OPCs becomes less robust, and axons remain chronically demyelinated. Chronic demyelination is thought to underlie axon loss, as loss of trophic support combined with the metabolic stress of transmitting impulses along a demyelinated membrane can lead to a breakdown of axonal integrity and permanent damage to the demyelinated circuit. In addition, exposure of a demyelinated axon to an inflammatory milieu, including infiltrating immune cells and activated microglial cells, is also thought to produce permanent damage and axonal loss. Axon loss as a result of demyelination is thought to underlie long term disease progression and disability in MS patients (see, Compston, et al., The Lancet, Vol. 359, 1221-1231, 2002 and D. Kremer et al, Trends in Neurosciences, Vol. 39, No. 4, 246-263, 2016).

The loss of remyelinating capacity in MS is not well understood, but is thought to involve a block in the differentiation capacity of OPCs, or the absence of a necessary signal present in the cell environment of the demyelinating lesion or in the demyelinated axons (see, R. Franklin et al., Nature Reviews/Neuroscience, Vol. 9, 839-855, 2008). The OPC cell population is prevalent in MS patients, but fails to generate new myelin in response to demyelination. Thus, a compound that can promote differentiation and myelination of OPCs should function to restore this regenerative capacity and blunt or reverse the degenerative effects of MS (see, Stangel, M. et al., Progress in Neurobiology, 68, 361-376, 2002, Nalm, F. J. et al., Nature (Letter), published online 20 Apr. 2015, doi:10.1038/nature14335). Such an agent could both increase the function of neurons and provide trophic support to enhance their survival (see, Mei, F. et al. Nature Medicine, Vol. 20, No. 8, 954-961, 2014).

Leukodystrophies are degenerative white matter diseases characterized by dysmyelination or demyelination. Multiple genetic or metabolic disorders can lead to progressive white matter damage in pediatric or adult populations resulting in severe motor or cognitive deficits, mental retardation or death. A compound that can delay myelin damage or promote repair of demyelinated axons could significantly alter the course of leukodystrophies and improve their outcome. Such a compound could be also useful in combination with other therapies that can correct the disease-specific defect, metabolic, genetic or other, responsible for initiating or maintaining the disease in order to accelerate repair, restore function or prevent further damage.

Hypoxic-ischemic insults leading to reduced oxygenation and blood supply into the brain can cause severe damage to OPCs, and demyelination. Periventricular leukomalacia is a condition characterized by toxic death of OPCs in the periventricular region and leading to severe dysmyelination and demyelination. This pathology has been proposed as the root cause of cerebral palsy, a life-long debilitating CNS disorder characterized by various motor and/or cognitive deficits of variable intensity. A compound promoting differentiation of surviving OPCs and remyelination of damaged areas could be used for the treatment or prevention of cerebral palsy in vulnerable infant populations.

Current therapies for MS are immunomodulatory in nature and do not directly promote repair. In addition, some of these immunomodulatory agents can leave patients vulnerable to opportunistic infection or neoplasia. Thus, there remains a need for compounds, such as those of the present invention, that can promote differentiation and myelination of OPCs and lead to the repair of demyelinated axons. Such a compound could also be useful in combination with existing or experimental immunmodulating and other relevant therapies to treat MS and other neurological and demyelinating diseases.

SUMMARY OF THE INVENTION

The present invention provides compounds or a pharmaceutically acceptable salt thereof and the methods, compositions and kits disclosed herein for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy. These compounds have the general formula I and I′:

or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides compounds of formula (I′)

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is CH or N;

X² is CR^(X2) or N;

X³ is CR³ or N;

where R³ and R^(X2) are each independently selected from the group consisting of hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, and cyano;

provided that X¹, X², and X³ are not simultaneously N, X² and X³ are not simultaneously N, and X¹ and X³ are not simultaneously N;

L¹ is a bond, —O—, —NR⁵—, —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, or —C(O)—, wherein R⁵ is hydrogen or C₁₋₄alkyl;

R¹ is -G¹-L²-R⁶, -G¹-L²-R⁷, G², G³, G⁴, G⁵, G⁶, or -≡-G⁵;

G¹ is i) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; or ii) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

L² is a bond, a —C₁₋₃alkylene-, or —C(O)—;

R⁶ is a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, and oxo; b) a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and hydroxyl; c) a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L², the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; or d) a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

R⁷ is a) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, and oxo; or b) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, and —C(O)OH;

G² is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G² being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₆alkylene-NH₂, —C₁₋₆alkylene-NH(C₁₋₄alkyl), —C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

G³ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L¹, the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G³ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

G⁴ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

G⁵ is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

G⁶ is a monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁶ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, —C(O)OC₁₋₄alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-OH, or G¹⁰, G¹⁰ being a C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen and optionally containing 1 double bond, G¹⁰ being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, and G²⁰, G²⁰ being a C₃₋₆cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G²⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; and

R⁴ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R⁴ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —NH(C₁₋₄alkylene-OC₁₋₄alkyl), —NH(C₁₋₄alkylene-OH), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OH), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH.

In another aspect, the present invention provides compounds of formula (I′), or a pharmaceutically acceptable salt thereof, wherein:

X¹ is CH or N;

X² is CR^(X2) or N;

X³ is CR³ or N;

where R³ and R^(X2) are each independently selected from the group consisting of hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, and cyano;

provided that X¹, X², and X³ are not simultaneously N, X² and X³ are not simultaneously N, and X¹ and X³ are not simultaneously N;

L¹ is a bond, —O—, —NR⁵—, —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, —C(O)—, —NR⁵C(O)—, —OC(O)—, —NR⁵C(O)NR⁵—, —NR⁵C(O)O—, —NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O—, wherein each R⁵ is independently hydrogen or C₁₋₄alkyl, and the C₁₋₄alkylene of —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O— is optionally substituted with 1-6 halogens;

R¹ is -G¹-L²-R⁶, -G¹-L²-R⁷, G², G³, G⁴, G⁵, G⁶, G⁷, or -≡-G⁵;

G¹ is i) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; or ii) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

L² is a bond, a —C₁₋₆alkylene-, —C(O)—, —O—, or —NR⁵—, wherein the —C₁₋₆alkylene- is optionally substituted with 1-6 halogens and 1-2 C₁alkylene units of the —C₁₋₆alkylene- are optionally replaced with —C(O)—, —O—, or —NR^(5′)—, wherein each R^(5′) is independently hydrogen or C₁₋₄alkyl;

R⁶ is a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; b) a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; c) a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L², the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; or d) a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH;

R⁷ is a) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; or b) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH;

G² is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G² being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C₁₋₆alkylene-cyano, —C(O)C₁₋₄alkyl, —C(O)—C₁₋₆alkylene-OC₁₋₄alkyl, —C(O)—C₁₋₆alkylene-OH, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene-NH₂, —C₁₋₆alkylene-NH(C₁₋₄alkyl), —C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —O—C₁₋₆alkylene-NH₂, —O—C₁₋₆alkylene-NH(C₁₋₄alkyl), —O—C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —O—C₁₋₆alkylene-OC₁₋₄alkyl, —O—C₁₋₆alkylene-OH, —C₁₋₄alkylene-O—C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-O—C₁₋₄alkylene-OH, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), —S(O)₁₋₂C₁₋₄alkyl, —C₁₋₆alkylene-S(O)₁₋₂C₁₋₄alkyl, and a —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl, —OC(O)C₁₋₄alkyl, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

G³ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L¹, the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G³ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

G⁴ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

G⁵ is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

G⁶ is a monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁶ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

G⁷ is aryl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, —C(O)OC₁₋₄alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-OH, or G¹⁰, G¹⁰ being a C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen and optionally containing 1 double bond, G¹⁰ being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, and G²⁰, G²⁰ being a C₃₋₆cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G²⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; and

R⁴ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R⁴ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —NH(C₁₋₄alkylene-OC₁₋₄alkyl), —NH(C₁₋₄alkylene-OH), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OH), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH.

In another aspect, the present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

X¹ and X² are independently CH or N, provided that both X¹ and X² are not simultaneously N;

L¹ is a bond, —O—, —NR⁵—, or —NR⁵—C₁₋₄alkylene-, wherein R⁵ is hydrogen or C₁₋₄alkyl;

R¹ is -G¹-L²-R⁶, -G¹-L²-R⁷, G², G³, G⁴ or G⁵;

G¹ is a 4- to 8-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo;

L² is a bond or a —C₁₋₃alkylene-;

R⁶ is: a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, and oxo; or b) a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and hydroxyl;

R⁷ is: a) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, and oxo; or b) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, and —C(O)OH;

G² is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G² being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), and —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

G³ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L¹, the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G³ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and oxo;

G⁴ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and oxo;

G⁵ is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl);

R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen and optionally containing 1 double bond, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl C₁₋₄haloalkyl, C₃₋₆cycloalkyl, and a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen;

R³ is hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, or cyano; and

R⁴ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R⁴ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH.

Another aspect of the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, which promote remyelination of demyelinated axons.

In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, which differentiate endogenous oligodendrocyte precursor cells.

In another aspect, the invention provides methods of treating multiple sclerosis by administering to a patient in need thereof a therapeutically effective amount of a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating, preventing or ameliorating one or more symptoms of a subject with multiple sclerosis or another neurological disease.

In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of multiple sclerosis, the promotion of remyelination of demyelinated axons, or the differentiation of endogenous oligodendrocyte precursor cells.

In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis, promoting remyelination of demyelinated axons, or differentiating endogenous oligodendrocyte precursor cells.

In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophyin.

In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof

In another aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.

The present invention also features kits comprising compounds of formula I or I′.

DETAILED DESCRIPTION OF THE INVENTION 1. Definitions

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables in formula I or I′ encompass specific groups, such as, for example, alkyl and cycloalkyl. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The phrase “optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

The compounds of the invention are defined according to the terms in the claims and the embodiments. The following definitions are provided as a general guide to understanding the claims and embodiments and are applicable where specific definitions are absent.

The term “alkyl” as used herein, means a straight or branched chain saturated hydrocarbon. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylene,” as used herein, means a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and —CH₂CH(CH₃)CH(CH₃)CH₂—.

The term “alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “aryl,” as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, or indenyl. The phenyl and bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl or bicyclic aryl.

The term “halogen” means a chlorine, bromine, iodine, or fluorine atom.

The term “haloalkyl,” as used herein, means an alkyl, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen. For example, representative examples of haloalkyl include, but are not limited to, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-1,1-dimethylethyl, and the like.

The term “haloalkoxy,” as used herein, means an alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. Representative examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, and pentafluoroethoxy.

The term “heteroaryl,” as used herein, means an aromatic heterocycle, i.e., an aromatic ring that contains at least one heteroatom. A heteroaryl may contain from 5 to 12 ring atoms. A heteroaryl may be a 5- to 6-membered monocyclic heteroaryl or an 8- to 12-membered bicyclic heteroaryl. A 5-membered monocyclic heteroaryl ring contains two double bonds, and one, two, three, or four heteroatoms as ring atoms. Representative examples of 5-membered monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl. A 6-membered heteroaryl ring contains three double bonds, and one, two, three or four heteroatoms as ring atoms. Representative examples of 6-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The bicyclic heteroaryl is an 8- to 12-membered ring system having a monocyclic heteroaryl fused to an aromatic, saturated, or partially saturated carbocyclic ring, or fused to a second monocyclic heteroaryl ring. Representative examples of bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzothienyl, indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridinyl, 5,6,7,8-tetrahydroquinolinyl, and 6,7-dihydro-5H-cyclopenta[b]pyridinyl. The heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the groups.

The term “cycloalkyl” as used herein, means a monocyclic all-carbon ring containing zero heteroatoms as ring atoms, and zero double bonds. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.

The term “cycloalkenyl” as used herein, means a monocyclic non-aromatic all-carbon 5- to 6-membered ring containing zero heteroatoms as ring atoms and one double bond. Examples of cycloalkenyl include cyclopentenyl and cyclohexenyl. The cycloalkenyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.

The terms “heterocycle” or “heterocyclic” refer generally to ring systems containing at least one heteroatom as a ring atom where the heteroatom is selected from oxygen, nitrogen, and sulfur. In some embodiments, a nitrogen or sulfur atom of the heterocycle is optionally substituted with oxo. Heterocycles may be a monocyclic heterocycle, a fused bicyclic heterocycle, or a spiro heterocycle. The monocyclic heterocycle is generally a 4, 5, 6, 7, or 8-membered non-aromatic ring containing at least one heteroatom selected from O, N, or S. The 4-membered ring contains one heteroatom and optionally one double bond. The 5-membered ring contains zero or one double bond and one, two or three heteroatoms. The 6, 7, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 4,5-dihydroisoxazol-5-yl, 3,4-dihydropyranyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl, thiopyranyl, and trithianyl. The fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle fused to a phenyl, to a saturated or partially saturated carbocyclic ring, or to another monocyclic heterocyclic ring, or to a monocyclic heteroaryl ring. Representative examples of fused bicyclic heterocycle include, but are not limited to, 1,3-benzodioxol-4-yl, 1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, and 1,2,3,4-tetrahydroquinolinyl. Spiro heterocycle means a 4, 5-, 6-, 7-, or 8-membered monocyclic heterocycle ring wherein two of the substituents on the same carbon atom form a second ring having 3, 4, 5, 6, 7, or 8-members. Examples of a spiro heterocycle include, but are not limited to, 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and 8-azaspiro[4.5]decane. The monocyclic heterocycle groups of the present invention may contain an alkylene bridge of 1, 2, or 3 carbon atoms, linking two non-adjacent atoms of the group. Examples of such a bridged heterocycle include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, and oxabicyclo[2.2.1]heptanyl. The monocyclic, fused bicyclic, and spiro heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group. The foregoing description of heterocycles is merely illustrative. In the embodiments of the invention are set forth definitions for types of heterocycles at G¹, G², G³, G⁴, R², R⁴, and R⁶, and the substituents contained therein.

The term “oxo” as used herein refers to an oxygen atom bonded to the parent molecular moiety. An oxo may be attached to a carbon atom or a sulfur atom by a double bond. Alternatively, an oxo may be attached to a nitrogen atom by a single bond, i.e., an N-oxide.

Terms such as “alkyl,” “cycloalkyl,” “alkylene,” etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., “C₁₋₄alkyl,” “C₃₋₆cycloalkyl,” “C₁₋₄alkylene”). These designations are used as generally understood by those skilled in the art. For example, the representation “C” followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, “C₃alkyl” is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in “C₁₋₄,” the members of the group that follows may have any number of carbon atoms falling within the recited range. A “C₁₋₄alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds of formula I or I′. The structures also include zwitterioinc forms of the compounds or salts of formula I or I′ where appropriate.

2. Compounds

In a first aspect of the invention are provided compounds of formula (I′)

or a pharmaceutically acceptable salt thereof, wherein L¹, R¹, R², R⁴, X¹, X², and X³ are as defined herein.

In a second aspect of the invention are provided compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein L¹, R¹, R², R³, R⁴, X¹, and X² are as defined herein.

In some embodiments of the invention, L¹-R¹ is L¹-G¹-L²-R⁶, wherein L¹, G¹, L², and R⁶ are as defined herein. L¹ and L² may be bonded to the same atom in G¹ (e.g.,

or L¹ and L² may be bonded to different atoms in G¹ (e.g.,

In some embodiments of the invention, R¹ is -G¹-L²-R⁶, wherein G¹, L², and R⁶ are as defined herein. R⁶ may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific R⁶, then R⁶ is unsubstituted.

In some embodiments R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, and oxo. In some embodiments R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH. For example, in some embodiments, R⁶ is an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl, a morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,4-oxazepanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, a pyrrolidinyl, piperidinyl, thiomorpholinyl, a thietanyl, piperazinyl, or azetidinyl, each being optionally substituted as described herein. In other embodiments, R⁶ is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, or thietanyl, each being optionally substituted with 1-4 substituents independently selected from C₁₋₄alkyl and oxo. In some embodiments, the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, piperazinyl, and azetidinyl, are each optionally substituted with 1-4 substituents independently selected from halogen, C₁₋₄alkyl and oxo. In some embodiments, the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, and piperazinyl are each optionally substituted with C₁₋₄alkyl, and the pyrrolidinyl, piperazinyl, and thietanyl further optionally substituted with 1-2 oxo groups. In other embodiments, R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1 oxygen atom (e.g., an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl). In other embodiments, R⁶ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with C₁₋₄alkyl or —CH₂S(O)₂phenyl. In other embodiments, R⁶ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with C₁₋₄alkyl. In other embodiments, R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1 sulfur atom (e.g., thietanyl, tetrahydrothiophenyl, tetrahydro-2H-thiopyranyl). In other embodiments, R⁶ is a 4-membered monocyclic heterocycle containing 1 sulfur atom and optionally substituted with 1-2 oxo groups. In other embodiments, R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1 nitrogen atom and optionally 1 oxygen atom or 1 sulfur atom (e.g., azetidinyl, pyrrolidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl) and optionally substituted with oxo (e.g., 2-oxopyrrolidin-1-yl). The heterocycles of R⁶ may be appended to the parent molecule (i.e., at L²) by any substitutable carbon atom or nitrogen atom. Thus, in some embodiments, the oxygen-containing heterocycle is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, or tetrahydropyran-4-yl. In other embodiments, the sulfur-containing heterocycle is thietan-3-yl, tetrahydrothiophen-3-yl, tetrahydro-2H-thiopyran-3-yl, or tetahydro-2H-thiopyran-4-yl. In other embodiments, the heterocycle containing 1 nitrogen atom and optionally 1 oxygen or sulfur atom is e.g., piperidin-1-yl, morpholin-4-yl, azetidin-1-yl, piperazin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 1,4-oxazepan-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, thiomorpholin-4-yl, or 2-oxopyrrolidin-1-yl. In the embodiments of the invention, the oxygen- and sulfur-containing heterocycles may be unsubstituted or substituted as described herein. For example, the oxygen-containing heterocycle may be oxetan-3-yl, 3-methyloxetan-3-yl or 3-((phenylsulfonyl)methyl)oxetan-3-yl and the sulfur-containing heterocycle may be thietan-3-yl or 1,1-dioxothietan-3-yl.

In other embodiments, R⁶ is a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, or hydroxyl. In other embodiments, R⁶ is a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH. For example, in some embodiments, R⁶ is a 5-membered heteroaryl containing 1-3 nitrogen atoms (e.g., pyrrolyl, imidazolyl, pyrazolyl, triazolyl). In certain embodiments, R⁶ is pyrazol-1-yl. In other embodiments, R⁶ is a 6-membered heteroaryl containing 1-3 nitrogen atoms (e.g., pyridine, pyrimidine, etc.).

In other embodiments, R⁶ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L², the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, the spirocyclic R⁶ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH. In some embodiments, R⁶ is a 7- to 12-membered spiro heterocycle consisting of the first ring and a second ring, as described herein. The first ring is attached to L² through any substitutable carbon or nitrogen atom. In one embodiment, the first ring is attached to L² through a nitrogen atom. The first ring of R⁶ includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine. In some embodiments, the first ring of R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom. For example, in some embodiments, the first ring is morpholino, piperazin-1-yl, or piperidin-1-yl. The second ring includes a C₃₋₈cycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl. The second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common. For example, in some embodiments, R⁶ is 4-oxa-7-azaspiro[2.5]octanyl (e.g., 4-oxa-7-azaspiro[2.5]octan-7-yl).

In other embodiments, R⁶ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo. In other embodiments, R⁶ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH. For example, in some embodiments, R⁶ is 2-oxa-5-azabicyclo[4.1.0]heptanyl (e.g., 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl).

In some embodiments of the invention, L¹-R¹ is L¹-G¹-L²-R⁷, wherein L¹, G¹, L², and R⁷ are as defined herein L¹ and L² may be bonded to the same atom in G¹, or L¹ and L² may be bonded to different atoms in G¹. In some embodiments of the invention, R¹ is -G¹-L²-R⁷. Unless substitution is indicated as present or optional for a specific R⁷, R⁷ is unsubstituted.

In some embodiments, R⁷ is a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, and oxo. In other embodiments, R⁷ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH. For example, in some embodiments, R⁷ is cyclopropyl, cyclobutyl, or cyclopentyl, each being optionally substituted with —C(O)OC₁₋₄alkyl, —C(O)OH, hydroxyl or 1-2 halogen. In one group of compounds, R⁷ is cyclopropyl. In another group of compounds R⁷ is cyclobutyl. In other embodiments, R⁷ is 3,3-difluorocyclobutyl. In other embodiments, R⁷ is a cyclobutane carboxylic acid.

In other embodiments, R⁷ is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, and —C(O)OH. In other embodiments, R⁷ is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH.

In some embodiments, G¹ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, G¹ is a 4- to 8-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, G¹ contains one nitrogen atom. In other embodiments, G¹ contains two nitrogen atoms. In some embodiments, G¹ is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms. The heterocycles at G¹ may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific heterocyclic G¹, the heterocycle is unsubstituted. For example, in some embodiments, G¹ may be piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-1H-pyrrolyl, oxetanyl, morpholino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl, each unsubstituted or substituted as described herein. In other embodiments, the piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-1H-pyrrolyl, oxetanyl, morpholino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl are optionally substituted with 1-4 substituents independently selected from 1 hydroxyl, 1-2 halogen, 1 oxo, and 1-4 C₁₋₄alkyl groups. In some embodiments, pyrrolidinyl and/or piperidinyl is optionally substituted with halogen, 1 hydroxyl, or 1 oxo and the piperazinyl is optionally substituted with oxo. In some embodiments, G¹ is piperazin-1-yl optionally substituted with oxo. In some embodiments, G¹ may have a C₁₋₃alkylene bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2.1]heptanyl). In other embodiments, G¹ is without a C₁₋₃alkylene bridge between two non-adjacent ring atoms. The heterocycles of G¹ may be appended to the parent molecule (i.e., at L¹) by any substitutable carbon or nitrogen atom. For example, non-limiting examples of G¹ include piperazin-1-yl, 2-oxo-piperazin-1-yl, homopiperazin-1-yl, azetidin-1-yl, azetidin-3-yl, pyrrolidin-3-yl, 3-hydroxy-pyrrolidin-3-yl, 3-fluoro-pyrrolidin-3-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, 3-hydroxypiperidin-4-yl, 4-hydroxypiperidin-4-yl, 3-fluoropiperidin-4-yl, 4-fluoropiperidin-4-yl, 3,3-difluoropiperidin-4-yl, azepan-3-yl, 2, 5-diazabicyclo[2.2.1]heptan-2-yl, 2, 5-dihydro-1H-pyrrol-3-yl, or 1,2,3,6-tetrahydropyridin-4-yl.

L² is a bond, a —C₁₋₃alkylene- (e.g., CH₂), or a —C(O)— that links G¹ with R⁶ or R⁷. L² may be attached at any substitutable nitrogen or carbon atom of G¹ and any substitutable carbon or nitrogen atom of R⁶ or carbon atom of R⁷.

In other embodiments, L² is a bond, a —C₁₋₆alkylene- (e.g., —CH₂—, —CH₂CH₂CH₂—), —C(O)—, —O—, or —NR⁵—, wherein the —C₁₋₆alkylene- is optionally substituted with 1-6 halogens (e.g., fluoro) and 1-2 C₁alkylene units of the —C₁₋₆alkylene- are optionally replaced with —C(O)—, —O—, or —NR⁵— (e.g., —CH₂OCH₂—, —OCH₂CH₂—), wherein each R⁵ is independently hydrogen or C₁₋₄alkyl. In some embodiments, L² is C₁₋₃alkylene.

In other embodiments, G¹ is a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo. For example, in some embodiments, G¹ may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

In some embodiments, R¹ is -G¹-L²-R⁶ where G¹ is the monocyclic heterocycle and R⁶ is one of the heterocyclic groups a), b), c) or d). In other embodiments, G¹ is the cycloalkyl and R⁶ is one of the heterocyclic groups a), b), c) or d).

For example, in some embodiments -G¹-L²-R⁶ together may represent 4-(oxetan-3-yl)piperazin-1-yl, 4-(3-methyloxetan-3-yl)piperazin-1-yl, 4-(tetrahydrofuran-3-yl)piperazin-1-yl, 4-(2-methyltetrahydrofuran-3-yl)piperazin-1-yl, 4-(tetrahydro-2H-pyran-3-yl)piperazin-1-yl, 4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl, 4-((3-methyloxetan-3-yl)methyl)piperazin-1-yl, 4-(oxetan-3-yl)-2-oxo-piperazin-1-yl, 4-(oxetan-3-yl)piperidin-1-yl, 1-(oxetan-3-yl)piperidin-3-yl, 1-(oxetan-3-yl)piperidin-4-yl, 1-(3-methyloxetan-3-yl)piperidin-4-yl, 1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl, 3-hydroxy-1-(oxetan-3-yl)piperidin-4-yl, 3-fluoro-1-(oxetan-3-yl)piperidin-4-yl, 4-hydroxy-1-(oxetan-3-yl)piperidin-4-yl, 4-fluoro-1-(oxetan-3-yl)piperidin-4-yl, 3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl, 4-(2-oxopyrrolidin-1-yl)piperidin-1-yl, 3-(2-oxopyrrolidin-1-yl)piperidin-1-yl, 4-morpholinopiperidin-1-yl, (4-methylpiperazin-1-yl)piperidin-1-yl, 4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl, 3-morpholinopyrrolidin-1-yl, 1-(oxetan-3-yl)pyrrolidin-3-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl, 3-hydroxy-1-(oxetan-3-yl)-pyrrolidin-3-yl, 3-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl, 1-(oxetan-3-yl)azetidin-3-yl, 3-(oxetan-3-yl)azetidin-1-yl, 3-(pyrrolidin-1-yl)azetidin-1-yl, 3-(4-fluoropiperidin-1-yl)azetidin-1-yl, 3-morpholinoazetidin-1-yl, 3-methyl-3-morpholinoazetidin-1-yl, 3-(2-methylmorpholino)azetidin-1-yl, 3-(3-methylmorpholino)azetidin-1-yl, dimethylmorpholino)azetidin-1-yl, 3-(2,6-dimethylmorpholino)azetidin-1-yl, 3-(morpholine-4-carbonyl)azetidin-1-yl, 3-(pyrrolidine-1-carbonyl)azetidin-1-yl, 3-(1,4-oxazepan-4-yl)azetidin-1-yl, 3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)azetidin-1-yl, (3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)azetidin-1-yl, 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)azetidin-1-yl, 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)azetidin-1-yl, 3-(4-oxa-7-azaspiro[2.5]octan-7-yl)azetidin-1-yl, 3-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)azetidin-1-yl, 3-(morpholinomethyl)azetidin-1-yl), 3-(1,1-dioxidothiomorpholino)azetidin-1-yl, 4-(thietan-3-yl)piperazin-1-yl, 4-(piperazin-1-yl)thietane 1,1-dioxide, or 4-(oxetan-3-yl)-4-(λ¹-oxidanyl)-4λ⁴-piperazin-1-yl, 3-(1H-pyrazol-1-yl)azetidin-1-yl, 4-(oxetan-3-yl)morpholin-2-yl, 6-methyl-4-(oxetan-3-yl)morpholin-2-yl, 5-methyl-4-(oxetan-3-yl)morpholin-2-yl, 2-methyl-4-(oxetan-3-yl)morpholin-2-yl, 4-(oxetan-3-yl)-1,4-diazepan-1-yl, or 3-morpholinocyclobutyl.

In some embodiments, R¹ is -G¹-L²-R⁷ where G¹ is the monocyclic heterocycle and R⁷ is the cycloalkyl group a) or the phenyl group.

In other embodiments, -G¹-L²-R⁷ together may represent 3-(1-hydroxycyclobutyl)piperazin-1-yl; 4-cyclopropylpiperazin-1-yl; 4-cyclobutylpiperazin-1-yl; 4-cyclopentylpiperazin-1-yl; 1-cyclopropylpiperidin-4-yl; 1-cyclopropylpiperidin-3-yl; 1-cyclobutylpiperidin-4-yl, 1-cyclopentylpiperidin-4-yl, 4-(3,3-difluorocyclobutyl)piperazin-1-yl; or 5-cyclopropyl-2, 5-diazabicyclo[2.2.1]heptan-2-yl.

In other embodiments of the invention, R¹ is G² where G² is as described above. The heterocycles at G² may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific heterocyclic G², the heterocycle is unsubstituted. The optional G² substituent may be bonded to the same atom, or a different atom, in G², to which L¹ is bonded. For example, in some embodiments, G² may be morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, oxazolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2,5-dihydro-1H-pyrrolyl, 1,2,3,6-tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,5-dihydrofuranyl, or 3,6-dihydro-2H-pyranyl, each being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl), C₁₋₄haloalkyl (e.g., —CF₃, —CH₂CF₃, —CH₂CHF₂), halogen (e.g., fluoro), hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl (e.g., —C(O)CH₃), —C(O)C₃₋₆cycloalkyl (e.g., —C(O)cyclopropyl), —C(O)OC₁₋₄alkyl (e.g., —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OC(CH₃)₃), —C(O)OC₁₋₄haloalkyl (e.g., —C(O)OCH₂CF₃), —C(O)NH₂, —C(O)NH(C₁₋₄alkyl) (e.g., —C(O)NHCH₂CH₃), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g., —C(O)N(CH₃)₂), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl) (e.g., —C(O)NH(CH₂CH₂OCH₃)), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl) (e.g., —C(O)NCH₃(CH₂CH₂OCH₃)), —C(O)NH(—C₁₋₆alkylene-OH) (e.g., —C(O)NH(CH₂CH₂OH)), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH) (e.g., —C(O)NCH₃(CH₂CH₂OH)), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl) (e.g., —NH(CH₂CH₂OCH₃)), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl) (e.g., —NCH₃(CH₂CH₂OCH₃)), —NH(—C₁₋₆alkylene-OH) (e.g., —NH(CH₂CH₂OH)), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH) (e.g., —NCH₃(CH₂CH₂OH)), —C(O)C₁₋₄haloalkyl (e.g., —C(O)CF₃), —OC₁₋₄alkyl (e.g., —OCH₃), —C₁₋₆alkylene-OC₁₋₄alkyl (e.g., —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃), —C₁₋₆alkylene-OH (e.g., —CH₂OH, —C (OH)(CH₃)₂, —CH₂C(OH)(CH₃)₂, —C(OH)(CH₃)CH(CH₃)₂), —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl (e.g., —CH(CH₂OH)₂, —C(CH₃)(CH₂OH)₂, —C(CH₃)(CH₂OC(O)CH₃)₂, —C(CH₃)(CH₂OH)(CH₂OC(O)CH₃)), —C₁₋₆alkyl-NH₂, —C₁₋₆alkyl-NH(C₁₋₄alkyl), —C₁₋₆alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g., —CH₂CH₂—N(CH₃)₂, —CH₂CH₂CH₂—N(CH₃)₂), —C₁₋₄alkylene-C(O)OC₁₋₄alkyl (e.g., —CH₂C(O)OCH₂CH₃), —C₁₋₄alkylene-C(O)OH (e.g., —CH₂C(O)OH), —C(CH₃)₂C(O)OH), —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl) (e.g., —N(CH₃)C(O)CH₃), —NH₂, —NH(C₁₋₄alkyl) (e.g., —NHCH₃), and —N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g., —N(CH₃)₂). In some embodiments, G² may be substituted with one substituent selected from the foregoing group and further optionally substituted with 1-3 substituents selected from the group consisting of C₁₋₄alkyl and halogen. In some embodiments, G² is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms and substituted with C₁₋₄alkyl. In some embodiments, G² is piperazin-1-yl optionally substituted with C₁₋₄alkyl. For example, G² may be 4-C₁₋₄alkyl-piperazin-1-yl. In other embodiments, G² may be unsubstituted. In some embodiments, G² may be an optionally substituted 4- to 8-membered monocyclic heterocycle containing one oxygen atom and optionally one double bond (e.g., oxetanyl, tetrahydrofuranyl, 2,5-dihydrofuranyl). In other embodiments, G² may be an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen and optionally a second nitrogen atom, an oxygen or sulfur atom, and optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms (e.g., azetidinyl, piperidinyl, piperazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2,5-dihydro-1H-pyrrolyl, morpholinyl). For example, G² may be morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-1H-pyrrolyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 1,2,3,6-tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,5-dihydrofuranyl, or 3,6-dihydro-2H-pyranyl. In some embodiments, G² may have a C₁₋₃alkylene bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl). In other embodiments, G² is without a C₁₋₃alkylene bridge between two non-adjacent ring atoms. The heterocycles of G² may be appended to the parent molecule (i.e., at L¹) by any substitutable carbon or nitrogen atom (e.g., morpholin-4-yl, homomorpholin-4-yl, thiomorpholin-4-yl, 4-thiomorpholine 1,1-dioxide, piperazin-1-yl, homopiperazin-1-yl, azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, 2-oxooxazolidin-3-yl, 2-oxooxazolidin-5-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, azepan-1-yl, azepan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 2,5-dihydro-1H-pyrrol-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 2,5-dihydrofuran-3-yl, and 3,6-dihydro-2H-pyran-4-yl).

In some embodiments, G² is morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, oxazolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2,5-dihydro-1H-pyrrolyl, 1,2,3,6-tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,5-dihydrofuranyl, or 3,6-dihydro-2H-pyranyl, each being optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₆alkylene-NH₂, —C₁₋₆alkylene-NH(C₁₋₄alkyl), —C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl), and further optionally substituted with 1-3 substituents selected from the group consisting of C₁₋₄alkyl and halogen.

In some embodiments, G² is morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, oxazolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2,5-dihydro-1H-pyrrolyl, 1,2,3,6-tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,5-dihydrofuranyl, or 3,6-dihydro-2H-pyranyl, each being optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C₁₋₆alkylene-cyano (e.g., —CH₂CN), —C(O)C₁₋₄alkyl, —C(O)—C₁₋₆alkylene-OC₁₋₄alkyl (e.g., —C(O)CH₂OCH₃), —C(O)—C₁₋₆alkylene-OH, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl (e.g., —OCH₂CH₂F, —OCF₃), —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene-NH₂, —C₁₋₆alkylene-NH(C₁₋₄alkyl), —C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —O—C₁₋₆alkylene-NH₂, —O—C₁₋₆alkylene-NH(C₁₋₄alkyl), —O—C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g., —OCH₂CH₂N(CH₃)₂), —O—C₁₋₆alkylene-OC₁₋₄alkyl (e.g., —OCH₂CH₂OCH₂CH₃), —O—C₁₋₆alkylene-OH, —C₁₋₄alkylene-O—C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-O—C₁₋₄alkylene-OH (e.g., —CH₂CH₂OCH₂CH₂OH), —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), —S(O)₁₋₂C₁₋₄alkyl (e.g., S(O)₂CH₃), —C₁₋₆alkylene-S(O)₁₋₂C₁₋₄alkyl (e.g., —CH₂S(O)₂CH₃), and a —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl, —OC(O)C₁₋₄alkyl, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g., CH₂CH(OH)CH₂N(CH₃)₂, CH₂CH(OH)CH₂OCH₂CH₃), and further optionally substituted with 1-3 substituents selected from the group consisting of C₁₋₄alkyl and halogen.

In some embodiments, G² may be morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, oxazolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2,5-dihydro-1H-pyrrolyl, 1,2,3,6-tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,5-dihydrofuranyl, or 3,6-dihydro-2H-pyranyl, each being optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl), and further optionally substituted with 1-3 substituents selected from the group consisting of C₁₋₄alkyl and halogen.

In other embodiments, G² may be piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, 3-fluoropiperidin-1-yl, 4-fluoropiperidin-1-yl, 3-methoxypiperidin-1-yl, 3-(methoxymethyl)piperidin-1-yl, 4-(methoxymethyl)piperidin-1-yl, 4-methylpiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 1-acetylpiperidin-3-yl, 4-(ethoxycarbonyl)piperidin-1-yl, 4-(tert-butoxycarbonyl)piperidin-1-yl, 4-(ethylcarbamoyl)piperidin-1-yl, 1-methylpiperidin-3-yl, 3-cyanopiperidin-1-yl, 4-cyanopiperidin-1-yl, 1-(methoxycarbonyl)piperidin-3-yl, 1-(methoxycarbonyl)piperidin-4-yl, 3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl, 3-(hydroxymethyl)piperidin-1-yl, 1-(3-methoxypropyl)piperidin-4-yl, 4-(2-methoxyethyl)piperidin-1-yl, 1-acetylpiperidin-4-yl, 3-hydroxypiperidin-4-yl, pyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, 3-fluoro-1-methylpyrrolidin-3-yl, 3-hydroxy-1-methylpyrrolidin-3-yl, 1-acetylpyrrolidin-3-yl, 1-(2,2-difluoroethyl)pyrrolidin-3-yl, 3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl, 3-(methylamino)pyrrolidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3-(N-methylacetamido)pyrrolidin-1-yl, 2-oxooxazolidin-3-yl, 5-methyl-2-oxooxazolidin-5-yl, 3,5-dimethyl-2-oxooxazolidin-5-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-(tert-butyl)piperazin-1-yl, 3-(2-hydroxypropan-2-yl)piperazin-1-yl, 4-(ethoxycarbonyl)piperazin-1-yl, 4-(methoxycarbonyl)piperazin-1-yl, 4-((2,2,2-trifluoroethoxy)carbonyl)piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-(ethylcarbamoyl)piperazin-1-yl, 2,4,5-trimethylpiperazin-1-yl, 3,3,4-trimethylpiperazin-1-yl, 4-(2,2,2-trifluoroacetyl)piperazin-1-yl, piperazin-1-yl, 3-(trifluoromethyl)piperazin-1-yl, 4-(2-carboxypropan-2-yl)piperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl, 3,4,5-trimethylpiperazin-1-yl, 3-(2-hydroxy-3-methylbutan-2-yl)piperazin-1-yl, 2,5-dimethylpiperazin-1-yl, 3,4-dimethylpiperazin-1-yl, 3-methylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, 3-(hydroxymethyl)-4-methylpiperazin-1-yl, 4-(1-acetoxy-3-hydroxy-2-methylpropan-2-yl)piperazin-1-yl, 4-(1,3-diacetoxy-2-methylpropan-2-yl)piperazin-1-yl, 4-(1,3-dihydroxy-2-methylpropan-2-yl)piperazin-1-yl, 3-(hydroxymethyl)piperazin-1-yl, 4-(tert-butoxycarbonyl)piperazin-1-yl, 2-oxopiperazin-1-yl, 3-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl, 4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl, 4-(carboxymethyl)piperazin-1-yl, 4-(2-ethoxy-2-oxoethyl)piperazin-1-yl, (3-methoxypropyl)piperazin-1-yl, 2-(dimethylamino)ethyl)piperazin-1-yl, 3-(dimethylamino)propyl)piperazin-1-yl, 4-methyl-1,4-diazepan-1-yl, 4-acetyl-1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, morpholin-4-yl, 2,6-dimethylmorpholino, 2-(methoxymethyl)morpholino, 1,1-dioxidothiomorpholino, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 2,5-dihydrofuran-3-yl, tetrahydrofuran-3-yl, 2-methyltetrahydrofuran-2-yl, oxetan-3-yl, 3-hydroxyoxetan-3-yl, 3-methyloxetan-3-yl, azetidin-1-yl, azetidin-3-yl, 3-aminoazetidin-1-yl, 3-methylazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 3-ethyl-3-hydroxyazetidin-1-yl, 3-hydroxy-3-isopropylazetidin-1-yl, 3-fluoroazetidin-1-yl, 3-(methoxymethyl)azetidin-1-yl, 3-(hydroxymethyl)azetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, 3-(2-hydroxypropan-2-yl)azetidin-1-yl, 3-cyanoazetidin-1-yl, 3-(dimethylcarbamoyl)azetidin-1-y, 3-(diethylcarbamoyl)azetidin-1-y, 3-((2-methoxyethyl)(methyl)carbamoyl)azetidin-1-yl, 3-((1-methoxypropan-2-yl)carbamoyl)azetidin-1-yl, 3-((2-hydroxyethyl)amino)azetidin-1-yl, 3-((2-methoxyethyl)amino)azetidin-1-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or 5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl.

In other embodiments of the invention, R¹ is G³, where G³ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L¹, the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G³ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo. Unless substitution is indicated as present or optional for a specific spiro heterocyclic G³, the spiro heterocycle is unsubstituted. In some embodiments, G³ is a 7- to 12-membered spiro heterocycle consisting of the first ring and a second ring, as described herein. The first ring of G³ includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine. In a preferred embodiment, the first ring of G³ is a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom. In another embodiment, the first ring of G³ is a 4- to 6-membered monocyclic heterocycle containing 1-2 nitrogen atoms. The first ring is attached to L¹ through any substitutable carbon or nitrogen atom. In one embodiment, the first ring is attached to L¹ through a nitrogen atom. For example, in some embodiments, the first ring is azetidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl, or piperidin-1-yl. The second ring of G³ includes, but is not limited to, heterocycles such as oxetane, tetrahydrofuran, tetrahydropyran, dioxolane, etc. In some embodiments, the second ring has one oxygen atom. In other embodiments, the second ring has two oxygen atoms. In other embodiments, the second ring is a C₃₋₈cycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl. The second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common. For example, the second ring may be joined with the first ring at the 4-position of a first ring piperidin-1-yl or the 3-position of a first ring azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or piperazin-1-yl. In certain embodiments, G³ is 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 1-oxa-8-azaspiro[4.5]decanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-8-azaspiro[4.5]decanyl, or 2,6-diazaspiro[3.3]heptanyl, where the 2-oxa-5,8-diazaspiro[3.5]nonanyl is optionally substituted with C₁₋₄alkyl and/or oxo. In other embodiments, G³ is 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, the 2-oxa-5,8-diazaspiro[3.5]nonanyl being optionally substituted with C₁₋₄alkyl and oxo. The heterocycles of G³ may be appended to the parent molecule (i.e., at L) by any substitutable carbon or nitrogen atom. Other embodiments include 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 5-methyl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl, 1-oxa-8-azaspiro[4.5]decan-8-yl, 5-oxa-8-azaspiro[3.5]nonan-8-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-8-azaspiro[4.5]decan-8-yl, or 2,6-diazaspiro[3.3]heptan-2-yl.

In other embodiments of the invention, R¹ is G⁴, where G⁴ is as described above. The heterocycles at G⁴ may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific heterocyclic G⁴, the heterocycle is unsubstituted. For example, in some embodiments, G⁴ may be

each being optionally substituted with 1-4 substituents selected from the group consisting of C₁₋₄alkyl (e.g., methyl, ethyl, isobutyl), C₁₋₄haloalkyl (e.g., —CF₃, —CH₂CF₃), halogen (e.g., fluoro), hydroxyl, and oxo. In other embodiments G⁴ may be

each being optionally substituted with one C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, or oxo. In some embodiments, G⁴ may be substituted with one substituent selected from the foregoing group. For example, in some embodiments, G⁴ is

In other embodiments of the invention, R¹ is G⁵, where G⁵ is as described above. In some embodiments, G⁵ is cyclopropyl, cyclobutyl, or cyclopentyl, each optionally substituted as defined herein. For example, in some embodiments G⁵ is substituted with C₁₋₄alkoxy (e.g., 3-methoxycyclobutane). The optional G⁵ substituent may be bonded to the same atom, or a different atom, in G⁵, to which L¹ is bonded.

In some embodiments, R¹ is -≡-G⁵, where G⁵ is as described above. For example, in some embodiments, R¹ is -≡-cyclopropyl.

In some embodiments, R¹ is G⁶, where G⁶ is as described above. The heteroaryls at G⁶ may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific G⁶, the heteroaryl is unsubstituted. For example, in some embodiments, G⁶ may be optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl). For example, in some embodiments G⁶ may be a thiazole, oxazole, triazole or pyrazole optionally substituted with C₁₋₄alkyl or phenyl. Further exemplary G⁶ include 1-methyl-1H-1,2,4-triazol-3-yl, 1-ethyl-1H-1,2,4-triazol-3-yl, 1-phenyl-1H-1,2,4-triazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-phenyl-1H-pyrazol-3-yl, oxazol-2-yl, and thiazol-2-yl.

In some embodiments, R¹ is G⁷ where G⁷ is as described above. G⁷ may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific G⁷, is unsubstituted. In some embodiments, G⁷ is phenyl.

According to the embodiments described herein above and below are further combinations of embodiments wherein L¹ is a bond. In alternative combinations of embodiments, L¹ is —O—. In still further alternative combinations, L¹ is —NR⁵— and R⁵ is hydrogen or C₁₋₄alkyl. In still other embodiments, L¹ is —NR⁵—C₁₋₄alkylene-, wherein R⁵ is hydrogen or C₁₋₄alkyl. In other embodiments, L¹ is —O—C₁₋₄alkylene-. In other embodiments, L¹ is —C₁₋₄alkylene-. In other embodiments, L¹ is —C(O)—.

In still other embodiments, and combinations thereof, L¹ is a bond, —O—, —NR⁵—, —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, —C(O)—, —NR⁵C(O)—, —OC(O)—, —NR⁵C(O)NR⁵—, —NR⁵C(O)O—, —NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O—, wherein each R⁵ is independently hydrogen or C₁₋₄alkyl, and the C₁₋₄alkylene of —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O— is optionally substituted with 1-6 halogens (e.g., fluoro). For example, in some embodiments, each of the foregoing C₁₋₄alkylenes is optionally substituted with three fluoros.

In some embodiments, L¹-R¹ is —NR⁵—C₁₋₄alkylene-R¹, —O—C₁₋₄alkylene-R¹, —NR⁵C(O)—R¹, —OC(O)—R¹, —NR⁵C(O)O—R¹, —NR⁵—C₁₋₄alkylene-C(O)—R¹, —O—C₁₋₄alkylene-C(O)—R¹, —C₁₋₄alkylene-C(O)—R¹, —NR⁵C(O)—C₁₋₄alkylene-R¹, —OC(O)—C₁₋₄alkylene-R¹, —NR⁵C(O)NR⁵—C₁₋₄alkylene-R¹, —NR⁵C(O)O—C₁₋₄alkylene-R¹, or —NR⁵—C₁₋₄alkylene-O—R¹, wherein each R⁵ is independently hydrogen or C₁₋₄alkyl, and the C₁₋₄alkylene of —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O— is optionally substituted with 1-6 halogens. In other embodiments, the L¹ is reversed such that L¹-R¹ is R¹—NR⁵—C₁₋₄alkylene-, R¹—O—C₁₋₄alkylene-, R¹—NR⁵C(O)—, R¹—OC(O)—, R¹—NR⁵C(O)O—, R¹—NR⁵—C₁₋₄alkylene-C(O)—, R¹—O—C₁₋₄alkylene-C(O)—, R¹—C₁₋₄alkylene-C(O)—, R¹—NR⁵C(O)—C₁₋₄alkylene-, R¹—OC(O)—C₁₋₄alkylene-, R¹—NR⁵C(O)NR⁵—C₁₋₄alkylene-, R¹—NR⁵C(O)O—C₁₋₄alkylene-, or R¹—NR⁵—C₁₋₄alkylene-O—, wherein each R⁵ is independently hydrogen or C₁₋₄alkyl, and the C₁₋₄alkylene of —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O— is optionally substituted with 1-6 halogens.

Further in accordance with the embodiments described herein above and below are embodiments where X¹ and X² are each CH. In alternative embodiments, X¹ is N and X² is CH. In still other embodiments, X¹ is CH and X² is N. In other embodiments, X¹, X², and X³ are each CH. In other embodiments, X¹ is CH, X² is CR^(X2), and X³ is CR³. In other embodiments, X¹ is CH, X² is CR^(X2), and X³ is CH. In other embodiments, X¹ is CH, X² is C—F, and X³ is CH. In other embodiments, X¹ is CH, X² is CH, and X³ is CR³. In other embodiments, X¹ is N and X² and X³ and are CH. In other embodiments, X¹ is N, X² is CR^(X2), and X³ is CR³. In other embodiments, X¹ is CH, X² is N, and X³ is CH. In other embodiments, X¹ is CH, X² is N, and X³ is CR³. In other embodiments, X¹ and X² are CH, and X³ is N. In other embodiments, X¹ is CH, X² is CR^(X2), and X³ is N. In other embodiments, X¹ and X² are N, and X³ is CH. In other embodiments, X¹ and X² are N, and X³ is CR³.

R³ and R^(X2) are each independently selected from the group consisting of hydrogen, halogen (e.g, fluoro), C₁₋₄alkyl (methyl), C₁₋₄haloalkyl, —OC₁₋₄alkyl, or cyano.

Further according to each of the foregoing embodiments, R⁴ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R⁴ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen (e.g., fluoro, chloro), hydroxyl, cyano, —S(O)₂C₁₋₄alkyl (e.g., —SO₂CH₃), —S(O)C₁₋₄alkyl (e.g., —SOCH₃), —SC₁₋₄alkyl (e.g., —SCH₃), C₁₋₄alkyl (e.g., methyl, ethyl), C₁₋₄haloalkyl (e.g., —CF₃), —OC₁₋₄alkyl (e.g., —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂), —OC₁₋₄haloalkyl (e.g., —OCF₃), —C₁₋₄alkylene-OC₁₋₄alkyl (e.g., —CH₂OCH₃), —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g., —CH₂N(CH₃)(CH₂CH₃)), —NH(C₁₋₄alkylene-OC₁₋₄alkyl) (e.g., —NH(CH₂CH₂OCH₃)), —NH(C₁₋₄alkylene-OH) (e.g., —NH(CH₂CH₂OH)), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl) (e.g., —N(CH₃)(CH₂CH₂OCH₃)), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OH)(e.g., —N(CH₃)(CH₂CH₂OH)), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl)), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms (e.g., azetidin-1-yl, pyrrolidin-1-yl, azepan-1-yl), the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen (e.g., fluoro), hydroxyl, —OC₁₋₄alkyl (e.g., —OCH₃), C₁₋₄alkyl (e.g., ethyl), C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl (e.g., —CH₂OCH₃, —CH₂OCH₂CH₃), and —C₁₋₄alkylene-OH (e.g., —CH₂OH, —C(OH)(CH₃)₂). In further embodiments, R⁴ is phenyl, or a 6-membered heteroaryl such as pyrazinyl, pyrimidinyl, pyridazinyl, or pyridinyl, each optionally substituted as defined above. The 6-membered heteroaryl at R⁴ includes a pyridone ring, which is defined herein by the tautomeric hydroxypyridine form, whether or not the pyridone or the hydroxypyridine tautomer predominates. In some embodiments, R⁴ is phenyl, the phenyl being optionally substituted with one substituent selected from the group consisting of halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —NH(C₁₋₄alkylene-OC₁₋₄alkyl), —NH(C₁₋₄alkylene-OH), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OH), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH, and the phenyl being further optionally substituted with 1-2 substituents independently selected from the group consisting of halogen and C₁₋₄alkyl. In yet additional embodiments, R⁴ is phenyl, the phenyl being optionally substituted with one substituent selected from the group consisting of halogen, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, —OC₁₋₄alkyl, C₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH, and the phenyl being further optionally substituted with 1-2 substituents independently selected from the group consisting of halogen and C₁₋₄alkyl. Alternatively, R⁴ is pyrazinyl, the pyrazinyl being optionally substituted with 1-3 C₁₋₄alkyl groups. In another alternative, R⁴ is pyrimidinyl (e.g., pyrimidin-4-yl, pyrimidin-5-yl), the pyrimidinyl being optionally substituted with one substituent selected from halogen, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, —OC₁₋₄alkyl, or —C₁₋₄alkylene-OC₁₋₄alkyl, the pyrimidinyl being further optionally substituted with C₁₋₄alkyl. In still a further alternative, R⁴ is pyridazinyl (e.g., pyridazin-4-yl). In another alternative, R⁴ is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), the pyridinyl being optionally substituted with one substituent selected from the group consisting of halogen, hydroxyl, C₁₋₄alkyl, and a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the pyridinyl being further optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl.

In further embodiments according to the foregoing, R⁴ is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen and C₁₋₄alkyl. For example, in certain embodiments, R⁴ is phenyl optionally substituted with 1-2 fluoro atoms or 1 fluoro and 1 methyl group. In certain embodiments, R⁴ is independently any of phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, or 3-fluoro-5-methylphenyl.

In further embodiments according to the foregoing, R⁴ is pyrazine, which is unsubstituted.

R² is C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, t-butyl), C₁₋₄haloalkyl (e.g., CF₃, CHF₂), halogen (e.g., fluoro, chloro, bromo), hydroxyl, cyano, —S(O)₂C₁₋₄alkyl (e.g., —S(O)₂CH₃), —S(O)C₁₋₄alkyl (e.g., —S(O)CH₃), —SC₁₋₄alkyl (e.g., —SCH₃), —OC₁₋₄alkyl (e.g., —OCH₃, —OCH(CH₃)₂), —OC₁₋₄haloalkyl (e.g., —OCF₃), —C(O)C₁₋₄alkyl (e.g., —C(O)CH₃), —C(O)OC₁₋₄alkyl (e.g., —C(O)OCH₃), —C(O)NH₂, —C(O)NH(C₁₋₄alkyl) (e.g., —C(O)NHCH₃), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-OC₁₋₄alkyl (e.g., —CH₂OCH₃), —C₁₋₄alkylene-OH (e.g., —CH₂OH), or G¹⁰, G¹⁰ being a C₃₋₆cycloalkyl (e.g., cyclopropyl), C₅₋₆cycloalkenyl (e.g., cyclopentenyl), or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from nitrogen and oxygen and optionally containing 1 double bond (e.g., tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 2,5-dihydrofuran-3-yl, oxetan-3-yl, morpholin-4-yl, azetidin-1-yl, piperazin-1-yl), G¹⁰ being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl (e.g., methyl), C₁₋₄haloalkyl, and G²⁰, G²⁰ being a C₃₋₆cycloalkyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from nitrogen and oxygen (e.g., oxetan-3-yl, morpholino), G²⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, R² may be G¹⁰-G²⁰, where G¹⁰ and G²⁰ are optionally substituted as described herein. In some embodiments, R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen or C₃₋₆cycloalkyl. In other embodiments, R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl. In other embodiments, R² is C₁₋₄alkyl or C₁₋₄haloalkyl. In other embodiments, R² is a 4- to 8-membered monocyclic heterocycle containing 1 to 2 nitrogen atoms (e.g., azetidine, piperazine) optionally substituted with a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from nitrogen and oxygen (e.g., oxetane, morpholine). In one group of compounds, R² is methyl, ethyl, fluoro, trifluoromethyl, difluoromethyl, or cyclopropyl. In another group of compounds, R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl.

In still other embodiments, X¹ and X² are each CH and R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from nitrogen and oxygen and optionally containing 1 double bond, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl, and C₁₋₄haloalkyl; or X¹ is N, X² is CH and R² is C₁₋₄alkyl, halogen, C₃₋₆cycloalkyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from nitrogen and oxygen and optionally containing 1 double bond, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl, and C₁₋₄haloalkyl; or X¹ is CH, X² is N, and R² is C₁₋₄alkyl.

In other embodiments, X¹ and X² are each CH and R² is C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, t-butyl), C₁₋₄haloalkyl (e.g., CF₃, CHF₂), halogen (e.g., fluoro, chloro, bromo), cyano, —S(O)₂C₁₋₄alkyl (e.g., —S(O)₂CH₃), —SC₁₋₄alkyl (e.g., —SCH₃), —OC₁₋₄alkyl (e.g., —OCH₃), —OC₁₋₄haloalkyl (e.g., —OCF₃), C₃₋₆cycloalkyl (e.g., cyclopropyl), or a 4- to 6-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from nitrogen and oxygen and optionally containing 1 double bond (e.g., tetrahydropyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 2,5-dihydrofuran-3-yl, oxetan-3-yl, morpholin-4-yl); or X¹ is N, X² is CH, and R² is C₁₋₄alkyl (e.g. methyl), halogen (e.g., chloro), C₃₋₆cycloalkyl (e.g., cyclopropyl), or a 6-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from nitrogen and oxygen (e.g., morpholin-4-yl); or X¹ is CH, X² is N, and R² is C₁₋₄alkyl (e.g. methyl).

R³ is hydrogen, halogen (e.g., fluoro, chloro, bromo), C₁₋₄alkyl (e.g., methyl, ethyl), C₁₋₄haloalkyl (e.g., CF₃, CHF₂), —OC₁₋₄alkyl (e.g., —OCH₃), or cyano. In some embodiments of formula (I), X¹ and X² are each CH and R³ is hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, or cyano. In other embodiments, X¹ and X² are each CH and R³ is hydrogen, halogen, C₁₋₄alkyl, or —OC₁₋₄alkyl. In one group of compounds, X¹ and X² are each CH and R³ is hydrogen, fluoro, methyl, or methoxy. In other embodiments, X¹ and X² are as defined herein and R³ is hydrogen. In one group of compounds, X¹ and X² are each CH and R³ is hydrogen. In another group of compounds, X¹ is N, X² is CH, and R³ is hydrogen. In still another group of compounds, X¹ is CH, X² is N, and R³ is hydrogen.

In yet other embodiments, the invention provides particular combinations of L¹, R¹, R², R³, R⁴, X¹ and X².

In one embodiment, R¹ is -G¹-L²-R⁶, -G¹-L²-R⁷, or G²; L¹ is a bond; G¹ is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms; L² is a bond; R⁶ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with C₁₋₄alkyl; R⁷ is a cyclopropyl; G² is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms and substituted with C₁₋₄alkyl or G² is a 4-membered monocyclic heterocycle containing 1 oxygen atom; R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl; and X¹ and X² are each CH or X¹ is CH and X² is N. In one group of compounds, G¹ is piperazin-1-yl; L² is a bond; R⁶ is oxetan-3-yl or 3-methyloxetan-3-yl, each attached to the 4-position of the piperazin-1-yl of G¹; R⁷ is cyclopropyl attached to the 4-position of the piperazin-1-yl of G¹; G² is 4-methylpiperazin-1-yl or oxetan-3-yl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl; and X¹ and X² are each CH, or X¹ is CH and X² is N.

In another embodiment, R¹ is -G¹-L²-R⁶; L¹ is a bond; G¹ is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms; L² is a bond; R⁶ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with C₁₋₄alkyl; R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl; and X¹ and X² are each CH, or X¹ is CH and X² is N. In one group of compounds, G¹ is piperazin-1-yl; L² is a bond; R⁶ is oxetan-3-yl or 3-methyloxetan-3-yl, each attached to the 4-position of the piperazin-1-yl of G¹; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl; and X¹ and X² are each CH, or X¹ is CH and X² is N.

In another embodiment, R¹ is -G¹-L²-R⁷; L¹ is a bond; G¹ is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms; L² is a bond; R⁷ is a cyclopropyl; R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl; and X¹ and X² are each CH, or X¹ is CH and X² is N. In one group of compounds, G¹ is piperazin-1-yl; L² is a bond; R⁷ is cyclopropyl attached to the 4-position of the piperazin-1-yl of G¹; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl; and X¹ and X² are each CH, or X¹ is CH and X² is N.

In another embodiment, R¹ is G²; L¹ is a bond; G² is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms and substituted with C₁₋₄alkyl or G² is a 4-membered monocyclic heterocycle containing 1 oxygen atom; R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl; and X¹ and X² are each CH, or X¹ is CH and X² is N. In one group of compounds, G² is 4-methylpiperazin-1-yl or oxetan-3-yl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl; and X¹ and X² are each CH, or X¹ is CH and X² is N.

In some embodiments are compounds of formula (II), formula (III), formula (IV) or formula (V), wherein R¹, R², R³, R⁴, R⁵, X¹, and X² are as defined herein:

Included in compounds of formula (II) are compounds of formula (IIA), (IIB), (IIC), (IID), (IIE) and (IIF), wherein G¹, G², G³, G⁴, G⁵, R², R³, R⁴, R⁶, R⁷, X¹, and X² are as defined herein:

In some embodiments of formula (IIA), are compounds of formula (IIA-1), (IIA-2), (IIA-3), (IIA-4), (IIA-5), (IIA-6), (IIA-7), (IIA-8), or (IIA-9):

wherein R⁸ is hydrogen or C₁₋₄alkyl and G¹, R², R³, R⁴, X¹, and X² are as defined herein.

In some embodiments according to formula (IIA), (IIA-1), (IIA-2), (IIA-3), (IIA-4), (IIA-5), (IIA-6), (IIA-7), (IIA-8), or (IIA-9), G is

In another embodiment, G¹ is

and R⁸ is hydrogen or C₁₋₄alkyl. In a further embodiment, G¹ is

and R⁸ is hydrogen or methyl.

In another embodiment, the present invention features a compound of formula (IIA), (IIA-1), (IIA-2), (IIA-3), (IIA-4), (IIA-5), (IIA-6), (IIA-7), (IIA-8), or (IIA-9) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom

In other embodiments, compounds of formula (IIA-1) may be represented by the formulas (IIA-1.0) to (IIA-1.9):

wherein R⁹ is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, or oxo, m is an integer from 0 to 4, and R², R³, R⁴, R⁸, X¹, and X² are as defined herein.

In some embodiments, m is 0. In other embodiments, compounds of formulas (IIA-2), (IIA-3), (IIA-4), (IIA-5), (IIA-6), (IIA-7), (IIA-8), and (IIA-9) may be represented, respectively, by the formulas (IIA-2.0), (IIA-3.0), (IIA-4.0), (IIA-5.0), (IIA-6.0), (IIA-6.1), (IIA-6.2), (IIA-7.0), (IIA-8.0), (IIA-8.1), (IIA-8.2), and (IIA-9.0):

wherein m, R², R³, R⁴, R⁸, R⁹, X1, and X² are as defined herein.

In the compounds of formulas (IIA-1) to (IIA-9), (IIA-1.0) to (IIA-1.9), (IIA-2.0), (IIA-3.0), (IIA-4.0), (IIA-5.0), (IIA-6.0), (IIA-6.1), (IIA-6.2), (IIA-7.0), (IIA-8.0), (IIA-8.1), (IIA-8.2), and (IIA-9.0) are embodiments wherein R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl. In some embodiments, R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In further embodiments, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In other embodiments, the present invention features compounds of formulas (IIA-1) to (IIA-9), (IIA-1.0) to (IIA-1.9), (IIA-2.0), (IIA-3.0), (IIA-4.0), (IIA-5.0), (IIA-6.0), (IIA-6.1), (IIA-6.2), (IIA-7.0), (IIA-8.0), (IIA-8.1), (IIA-8.2), and (IIA-9.0) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIB), are compounds of formula (IIB-1), (IIB-2), (IIB-3), or (IIB-4):

wherein R^(10A) and R^(10B) are each, independently hydrogen or halogen (e.g., fluoro), or COOH; R^(10C) is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, or —C(O)OH; q is an integer from 0 to 4; R¹¹ is hydrogen or hydroxyl; and G¹, R², R³, R⁴, X¹, and X² are as defined herein. In some embodiments of formula (IIB-2), each of R^(10A), R^(10B), and R¹¹ is hydrogen. In other embodiments of formula (IIB-2), R¹¹ is hydroxyl and each of R^(10A) and R^(10B) is hydrogen. In yet other embodiments, R¹¹ is hydrogen and each of R^(10A) and R^(10B) is fluoro. In some embodiments according to formula (IIB-1), (IIB-2), (IIB-3) or (IIB-4), G¹ is

In one embodiment, G¹ is

In other embodiments, compounds of formula (IIB-1), (IIB-2), (IIB-3) or (IIB-4) may be represented by the formulas (IIB-1.0) to (IIB-1.3), (IIB-2.0) to (IIB-2.3), (IIB-3.0) to (IIB-3.1) or (IIB-4.0):

wherein R⁹ is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, or oxo, m and q are each independently an integer from 0 to 4; and R², R³, R⁴, R^(10A), R^(10B), X¹, and X² are as defined herein.

In the compounds of formulas (IIB-1), (IIB-2), (IIB-3), (IIB-4), (IIB-1.0) to (IIB-1.3), (IIB-2.0) to (IIB-2.3), (IIB-3.0) to (IIB-3.1) and (IIB-4.0) are embodiments wherein R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl. In some embodiments, R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In further embodiments, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In other embodiments, the present invention features compounds of formulas (IIB-1), (IIB-2), (IIB-3), (IIB-4), (IIB-1.0) to (IIB-1.3), (IIB-2.0) to (IIB-2.3), (IIB-3.0) to (IIB-3.1) and (IIB-4.0) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIC) are compounds of formula (IIC-1), (IIC-2), (IIC-3), (IIC-4), (IIC-5), (IIC-6), (IIC-7), (IIC-8), (IIC-9) and (IIC-10):

In each of formulas (IIC-1), (IIC-2), (IIC-3), (IIC-4), (IIC-5), (IIC-6), (IIC-7), (IIC-8), (IIC-9) and (IIC-10), R¹² represents the optional G² substitution, as defined herein, and n is an integer from 0-4. In the foregoing formulas, the illustrated G² groups having the following meanings: In compounds of formula (IIC-1),

is a 4-membered monocyclic heterocycle containing one nitrogen atom. In compounds of formula (IIC-2),

is a 5-membered monocyclic heterocycle containing one nitrogen atom and optionally one double bond. In compounds of formula (IIC-3),

is a 6-membered monocyclic hetereocycle containing one nitrogen and optionally a second nitrogen, one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-4),

is a 6-membered monocyclic hetereocycle containing one nitrogen and one oxygen atom or sulfur atom, and optionally one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-5),

is a 7-membered monocyclic hetereocycle containing one nitrogen and optionally a second nitrogen, one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-6),

is a 7-membered monocyclic hetereocycle containing one nitrogen and one oxygen atom or sulfur atom, and optionally one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-7),

is a 4-membered monocyclic heterocycle containing one oxygen atom. In compounds of formula (IIC-8),

is a 5-membered monocyclic heterocycle containing one oxygen atom and optionally one double bond. In compounds of formula (IIC-9),

is a 6-membered monocyclic hetereocycle containing one oxygen atom and optionally one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-10),

is a 5-membered monocyclic heterocycle containing one nitrogen and one oxygen atom or sulfur atom.

In other embodiments, the present invention features compounds of formulas (IIC-1), (IIC-2), (IIC-3), (IIC-4), (IIC-5), (IIC-6), (IIC-7), (IIC-8), (IIC-9) and (IIC-10) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In compounds of formula (IIC-1), are further compounds of formula (IIC-1.0) or (IIC-1.1), wherein R¹² and n are as defined herein:

In compounds of formula (IIC-2), are further compounds of formula (IIC-2.0), (IIC-2.1), or (IIC-2.2), wherein R¹² and n are as defined herein:

In compounds of formula (IIC-3), are further compounds of formula (IIC-3.0) to (IIC-3.5), wherein R¹² and n are as defined herein:

In compounds of formula (IIC-4), (IIC-5), and (IIC-6) are further compounds, respectively, of formula (IIC-4.0)-(IIC-4.2), (IIC-5.0), and (IIC-6.0), wherein R¹² and n are as defined herein:

In compounds of formula (IIC-1.1), (IIC-2.1), (IIC-2.2), (IIC-3.1)-(IIC-3.5), and (IIC-5.0) are embodiments where n is 1 and R¹² is attached to the available ring nitrogen atom. In some embodiments, the single R¹² is C₁₋₄alkyl, C₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, or —C₁₋₄alkylene-C(O)OH.

In compounds of formula (IIC-7), (IIC-8), (IIC-9) and (IIC-10) are further compounds, respectively, of formula (IIC-7.0), (IIC-8.0)-(IIC-8.1) (IIC-9.0)-(IIC-9.1) and (IIC-10.0)-(IIC-10.1), wherein R¹² and n are as defined herein:

In the compounds of formulas (IIC-1) to (IIC-10), (IIC-1.0), (IIC-1.1), (IIC-2.0), (IIC-2.1), (IIC-2.2), (IIC-3.0) to (IIC-3.5), (IIC-4.0), (IIC-4.1), (IIC-5.0), (IIC-6.0), (IIC-7.0), (IIC-8.0), (IIC-8.1), (IIC-9.0), (IIC-9.1), (IIC-10.0), and (IIC-10.1) are embodiments wherein R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl. In some groups of compounds in these embodiments, R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In further subgroups of compounds, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In some embodiments of formula (IIC), G² is

R⁹ is C₁₋₄alkyl, R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, and X² are as defined herein. In one embodiment, G² is

R⁹ is methyl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In another embodiment, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In other embodiments of formula (IIC), G² is oxetan-3-yl; R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, and X² are as defined herein. In some embodiment, G² is oxetan-3-yl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In other embodiments, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In some embodiments of formula (IID), G³ is

wherein R¹³ is hydrogen or an optional substituent of G³ (e.g., C₁₋₄alkyl such as methyl, ethyl). In some embodiments, R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, and X² are as defined herein. In some groups of compounds, G³ is

R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In some embodiments, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In some embodiments of formula (IIE), G⁴ is

each being optionally substituted with 1-4 substituents selected from the group consisting of C₁₋₄alkyl (e.g., methyl, ethyl, isobutyl), C₁₋₄haloalkyl (e.g., —CF₃, —CH₂CF₃), halogen (e.g., fluoro), and oxo. In one embodiment, G⁴ is

each being optionally substituted with one C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, or oxo. In some embodiments, R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, and X² are as defined herein. In other embodiments, G⁴ is

R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In some embodiment, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In other embodiments, the present invention features compounds of formulas (IIC-1) to (IIC-10), (IIC-1.0), (IIC-1.1), (IIC-2.0), (IIC-2.1), (IIC-2.2), (IIC-3.0) to (IIC-3.5), (IIC-4.0), (IIC-4.1), (IIC-5.0), (IIC-6.0), (IIC-7.0), (IIC-8.0), (IIC-8.1), (IIC-9.0), (IIC-9.1), (IIC-10.0), and (IIC-10.1) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

Included in compounds of formula (III) are compounds of formula (IIIA), (IIIB), (IIIC), (IIID), (IIIE) and (IIIF), wherein G¹, G², G³, G⁴, G⁵, R², R³, R⁴, X¹, and X² are as defined herein:

In some embodiments, the present invention features compounds of formulas (IIIA), (IIIB), (IIIC), (IIID), (IIIE) and (IIIF) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIIA), are compounds of formula (IIIA-1), wherein G¹, R², R³, R⁴, R⁸, X¹, and X² are as defined herein:

In some embodiments, compounds of formula (IIIA-1) may be represented by the formulas (IIIA-1.0) or (IIIA-1.1):

wherein R², R³, R⁴, X¹, and X² are as defined herein.

In some embodiments of formulas (IIIA) to (IIIF), (IIIA-1), (IIIA-1.0), or (IIIA-1.1), R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, and X² are as defined herein. In some embodiments, R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In other embodiments, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

Included in compounds of formula (IV) are compounds of formula (IVA), (IVB), (IVC), (IVD), (IVE) or (IVF), wherein G¹, G², G³, G⁴, G⁵, R², R³, R⁴, R⁵, X¹, and X² are as defined herein:

In some embodiments, the present invention features compounds of formulas (IVA), (IVB), (IVC), (IVD), (IVE) and (IVF) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IVA), are compounds of formula (IVA-1), wherein G¹, R², R³, R⁴, R⁵, R⁸, X¹, and X² are as defined herein:

In some embodiments, compounds of formula (IVA-1) may be represented by the formulas (IVA-1.0) or (IVA-1.1):

In some embodiments of formulas (IVA) to (IVF), (IVA-1), (IVA-1.0), or (IVA-1.1), R⁵ is H or methyl; R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, and X² are as defined herein. In some embodiments, R⁵ is H or methyl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, pyridine-3-yl, 2-fluoropyridin-4-yl, or pyrazin-2-yl. In subgroups of compounds X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In some embodiments of formula (IVC), are compounds of formula (IVC-1) (IVC-2), (IVC-3), or (IVC-4), wherein n, R², R³, R⁴, R⁵, R¹², X¹, and X² are as defined herein:

wherein R¹² represents the optional G² substitution, as defined herein, and n is an integer from 0-4. In some embodiments, R¹² is —C₁₋₄alkylene-OC₁₋₄alkyl or —C(O)C₁₋₄alkyl and n is 1. In a subgroup of compounds, n is 1 and R¹² is —C₁₋₄alkylene-OC₁₋₄alkyl or —C(O)C₁₋₄alkyl and is bonded to an available ring nitrogen atom. In compounds of formula (IVC-1),

is a 4-membered monocyclic heterocycle containing one nitrogen atom. In compounds of formula (IVC-2),

is a 6-membered monocyclic hetereocycle containing one nitrogen and optionally a second nitrogen, one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of (IVC-3),

is a 4-membered monocyclic heterocycle containing one oxygen atom. In compounds of formula (IVC-4),

is a 5-membered monocyclic heterocycle containing one oxygen atom and optionally one double bond.

In some embodiments, compounds of formula (IVC-1) (IVC-2), (IVC-3), and (IVC-4) may be represented by the formulas (IVC-1.0), (IVC-2.0), (IVC-2.1), (IVC-3.0), and (IVC-4.0):

wherein R^(12A) is H or R¹², and R², R³, R⁴, R⁵, R¹², X¹, and X² are as defined herein.

In some embodiments of formulas (IVC-1), (IVC-2), (IVC-3), (IVC-4), (IV-1.0), (IVA-2.0), (IVC-2.1), (IVC-3.0), or (IVC-4.0), R⁵ is H or methyl; R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl; and X¹ and X² are as defined herein. In some embodiments, R⁵ is H or methyl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, pyridine-3-yl, 2-fluoropyridin-4-yl, or pyrazin-2-yl. In subgroups of compounds X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In some embodiments of formula (IVF), are compounds of formula (IVF-1) and (IVF-2), wherein R¹⁴ is the optional substituent on G⁵, p is an integer from 0-4, and R², R³, R⁴, R⁵, X¹, and X² are as defined herein:

In some embodiments, compounds of formula (IVF-1) and (IVF-2) may be represented by the formulas (IVF-1.0) and (IVF-2.0):

In some embodiments of formulas (IVF-1), (IVF-2), (IVF-1.0) or (IVF-2.0), R⁵ is H or methyl; R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl; and X¹ and X² are as defined herein. In some embodiments, R⁵ is H or methyl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, pyridine-3-yl, 2-fluoropyridin-4-yl, or pyrazin-2-yl. In other embodiments, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

Included in compounds of formula (V) are compounds of formula (VA), (VB), (VC), (VD), (VE), or (VF), wherein G¹, G², G³, G⁴, G⁵, R², R³, R⁴, R⁵, X¹, and X² are as defined herein:

In some embodiments, the present invention features compounds of formulas (VA), (VB), (VC), (VD), (VE), and (VF) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (VC), are compounds of formula (VC-1)

wherein n, R², R³, R⁴, R⁵, R¹², X¹, and X² are as defined herein. R¹² represents the optional G² substitution, as defined herein, and n is an integer from 0-4. In compounds of formula (VC-1),

is a 5-membered monocyclic heterocycle containing one oxygen atom and optionally one double bond.

In some embodiments, compounds of formula (VC-1) may be represented by the formula (VC-1.0)

In some embodiments of formulas (VA) to VF), (VC-1) or (VC-1.0), R⁵ is H or methyl; R¹² is H or C₁₋₄alkyl, R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R³ is hydrogen; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl; and X¹ and X² are as defined herein. In some embodiments, R⁵ is H or methyl; R¹² is H or methyl, the C₁₋₄alkylene is —CH₂— or —CH₂CH₂—; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; R³ is hydrogen; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, pyridine-3-yl, 2-fluoropyridin-4-yl, or pyrazin-2-yl. In other embodiments, X¹ and X² are each CH; or X¹ is N and X² is CH; or X¹ is CH and X² is N.

In still other embodiments, the invention provides particular combinations of L¹, R¹, R², R⁴, X¹, X², and X³.

In some embodiments are compounds of formula (II′), formula (III′), formula (IV′), formula (V′), formula (VI′), formula (VII′), or formula (VIII′), wherein —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, R¹, R², R⁴, X¹, X², and X³ are as defined herein:

In some embodiments, the present invention features compounds of formulas (II′), formula (III′), formula (IV′), formula (V′), formula (VI′), formula (VII′), and formula (VIII′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In other embodiments, the present invention features compounds of formulas (IX′), (XI′), (XII′), (XIII′), and (XIV′), wherein —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, R¹, R², R⁴, X¹, X², and X³ are as defined herein and wherein one or more hydrogen atoms are optionally replaced by a deuterium atom.

In some embodiments of formulas (II′) to (VIII′) and (IX′), (XI′), (XII′), (XIII′), and (XIV′) are compounds where X² is CR^(X2) and R^(X2) is hydrogen or fluoro. In other embodiments, R^(X2) is fluoro.

Included in compounds of formula (II′) are compounds of formula (IIA′), (IIB′), (IIC′), (IID′), (IIE′), (IIF′), (IIG′), and (IIH′), wherein L², G¹, G², G³, G⁴, G⁵, G⁶, R², R⁴, R⁶, R⁷, X¹, X², and X³ are as defined herein:

In some embodiments, the present invention features compounds of formulas (IIA′), (IIB′), (IIC′), (IID′), (IIE′), (IIF′), (IIG′), and (IIH′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIA′), are compounds where L² is a bond having formula (IIA-1′) to (IIA-20′), wherein R^(8′) is C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, or oxo, s is an integer from 0-4, and G¹, R², R⁴, X¹, X², and X³, are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIA-1′) to (IIA-20′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments according to formula (IIA′), and (IIA-1′) to (IIA-20′), G¹ is

In another embodiment, G¹ is

R^(8′) is C₁₋₄alkyl or oxo, and s is an integer from 0 to 2. In a further embodiment, G¹ is

R^(8′) is methyl or oxo, and s is an integer from 0 to 2. In other embodiments, compounds of formula (IIA-1′) may be represented by the formulas (IIA-1.0′) to (IIA-1.11′), where R⁹ is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, or oxo, m is an integer from 0 to 4, and R², R⁴, R^(8′), X¹, X², and X³, are as defined herein. In some embodiments, m is 0. In some embodiments, R^(8′) is H or C₁₋₄alkyl (e.g., methyl). In some embodiments, G¹ is

m is 0, R^(8′) is H, R² is C₁₋₄alkyl (e.g., methyl), X¹ is CH, X² is CR^(X2), R^(X2) is F, and X³ is CH.

In some embodiments, the present invention features compounds of formulas (IIA-1.0′) to (IIA-1.11′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In other embodiments, compounds of formulas (IIA-2′) to (IIA-20′) may be represented, respectively, by the formulas (IIA-2.0′) to (IIA-20.0′) wherein m, s, R², R⁴, R^(8′), R⁹, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIA-2.0′) to (IIA-20.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIA′), are compounds of formula (IIA-100′) and (IIA-200′).

In some embodiments, the present invention features compounds of formula (IIA-100′) and (IIA-200′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formulas (IIA-100′) and (IIA-200′), G¹ is piperazinyl, piperidinyl, or azetidinyl, and R⁶ is oxetanyl, morpholino, or pyrrolidinyl. In other embodiments, G¹ is piperazin-1-yl, piperidin-1-yl, or azetidin-1-yl and R⁶ is oxetan-3-yl, morpholin-4-yl, or pyrrolidin-1-yl. In each of the foregoing instances, G¹ and R⁶ are optionally substituted as described herein.

In other embodiments, compounds of formulas (IIA-100′) and (IIA-200′), where L² is methylene or carbonyl, may be represented, respectively, by the formulas (IIA-100.0′) to (IIA-100.3′) and (IIA-200.0′) to (IIA-200.3′) wherein m, s, R², R⁴, R^(8′), R⁹, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIA-100.0′) to (IIA-100.3′) and (IIA-200.0′) to (IIA-200.3′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIB′), are compounds of formula (IIB-1′), (IIB-2′), (IIB-3′), or (IIB-4′):

wherein R^(10A) and R^(10B) are each independently hydrogen, halogen (e.g., fluoro), or COOH; R^(10C) is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, or —C(O)OH; q is an integer from 0 to 4; R¹¹ is hydrogen or hydroxyl; and G¹, R², R⁴, X¹, X², and X³ are as defined herein. In some embodiments of formula (IIB-2′), each of R^(10A), R^(10B), and R¹¹ is hydrogen. In other embodiments of formula (IIB-2′), R¹¹ is hydroxyl and each of R^(10A) and R^(10B) is hydrogen. In yet other embodiments, R¹¹ is hydrogen and each of R^(10A) and R^(10B) is fluoro. In some embodiments according to formula (IIB-1′), (IIB-2′), (IIB-3′) or (IIB-4′), G¹ is

In one embodiment, G¹ is

In some embodiments, the present invention features compounds of formulas (IIB-1′), (IIB-2′), (IIB-3′), and (IIB-4′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In other embodiments, compounds of formula (IIB-1′) to (IIB-4′) may be represented by the formulas (IIB-1.0′) to (IIB-1.3′), (IIB-2.0′) to (IIB-2.3′), (IIB-3.0′) to (IIB-3.1′) or (IIB-4.0′):

wherein R⁹ is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, or oxo, m and q are each independently an integer from 0 to 4; and R², R⁴, R^(10A), R^(10B), R^(10C), X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIB-1.0′) to (IIB-1.3′), (IIB-2.0′) to (IIB-2.3′), (IIB-3.0′) to (IIB-3.1′) and (IIB-4.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIC′) are compounds of formula (IIC-1′) to (IIC-10′):

In some embodiments, the present invention features compounds of formulas (IIC-1′), (IIC-2′), (IIC-3′), (IIC-4′), (IIC-5′), (IIC-6′), (IIC-7′), (IIC-8′), (IIC-9′) and (IIC-10′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In each of formulas (IIC-1′), (IIC-2′), (IIC-3′), (IIC-4′), (IIC-5′), (IIC-6′), (IIC-7′), (IIC-8′), (IIC-9′) and (IIC-10′), R¹² represents the optional G² substitution, as defined herein, and n is an integer from 0-4. In the foregoing formulas, the illustrated G² groups having the following meanings: In compounds of formula (IIC-1′),

is a 4-membered monocyclic heterocycle containing one nitrogen atom. In compounds of formula (IIC-2′),

is a 5-membered monocyclic heterocycle containing one nitrogen atom and optionally one double bond. In compounds of formula (IIC-3′),

is a 6-membered monocyclic hetereocycle containing one nitrogen and optionally a second nitrogen, one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-4′),

is a 6-membered monocyclic hetereocycle containing one nitrogen and one oxygen atom or sulfur atom, and optionally one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-5′),

is a 7-membered monocyclic hetereocycle containing one nitrogen and optionally a second nitrogen, one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-6′),

is a 7-membered monocyclic hetereocycle containing one nitrogen and one oxygen atom or sulfur atom, and optionally one double bond, and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-7′),

is a 4-membered monocyclic heterocycle containing one oxygen atom. In compounds of formula (IIC-8′),

is a 5-membered monocyclic heterocycle containing one oxygen atom and optionally one double bond. In compounds of formula (IIC-9′),

is a 6-membered monocyclic hetereocycle containing one oxygen atom and optionally one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms. In compounds of formula (IIC-10′),

is a 5-membered monocyclic heterocycle containing one nitrogen and one oxygen atom or sulfur atom.

In compounds of formula (IIC-1′), are further compounds of formula (IIC-1.0′) or (IIC-1.1′), wherein R¹² and n are as defined herein:

In some embodiments, the present invention features compounds of formulas (IIC-1.0′) and (IIC-1.1′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In compounds of formula (IIC-2′), are further compounds of formula (IIC-2.0′), (IIC-2.1′), or (IIC-2.2′), wherein R¹² and n are as defined herein:

In some embodiments, the present invention features compounds of formulas (IIC-2.0′), (IIC-2.1′), and (IIC-2.2′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In compounds of formula (IIC-3′), are further compounds of formula (IIC-3.0′) to (IIC-3.5′), wherein R¹² and n are as defined herein:

In some embodiments, the present invention features compounds of formulas (IIC-3.0′) to (IIC-3.5′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In compounds of formula (IIC-4′), (IIC-5′), and (IIC-6′) are further compounds, respectively, of formula (IIC-4.0′)-(IIC-4.6′), (IIC-5.0′), and (IIC-6.0′), wherein R¹² and n are as defined herein:

In some embodiments, the present invention features compounds of formulas (IIC-4.0′)-(IIC-4.6′), (IIC-5.0′), and (IIC-6.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In compounds of formula (IIC-1.1′), (IIC-2.1′), (IIC-2.2′), (IIC-3.1′)-(IIC-3.5′), and (IIC-5.0′) are embodiments where n is 1 and R¹² is attached to the available ring nitrogen atom. In some embodiments, the single R¹² is C₁₋₄alkyl, C₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)C₁₋₄haloalkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₆alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, or —C₁₋₄alkylene-C(O)OH.

In compounds of formula (IIC-7′), (IIC-8′), (IIC-9′) and (IIC-10′) are further compounds, respectively, of formula (IIC-7.0′), (IIC-8.0′)-(IIC-8.1′) (IIC-9.0′)-(IIC-9.1′) and (IIC-10.0′)-(IIC-10.1′), wherein R¹² and n are as defined herein:

In some embodiments, the present invention features compounds of formulas (IIC-7.0′), (IIC-8.0′)-(IIC-8.1′) (IIC-9.0′)-(IIC-9.1′) and (IIC-10.0′)-(IIC-10.1′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIC′), G² is

R⁹ is C₁₋₄alkyl, R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, X², and X³ are as defined herein. In one embodiment, G² is

R⁹ is methyl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl.

In other embodiments of formula (IIC′), G² is oxetan-3-yl; R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, X², and X³ are as defined herein. In some embodiments, G² is oxetan-3-yl; R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl.

In some embodiments of formula (IID′), G³ is

each being optionally substituted with 1-4 substituents selected from the group consisting of C₁₋₄alkyl (e.g., methyl, ethyl, isobutyl), C₁₋₄haloalkyl (e.g., —CF₃, —CH₂CF₃), halogen (e.g., fluoro), and oxo (i.e., the optional substituent of G³). In some embodiments, R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, X², and X³ are as defined herein. In some groups of compounds, G³ is

where R¹³ is H or the optional substituent of G³ (e.g., C₁₋₄alkyl such as methyl, ethyl).

In some embodiments of formula (IIE′), G⁴ is

each being optionally substituted with 1-4 substituents selected from the group consisting of C₁₋₄alkyl (e.g., methyl, ethyl, isobutyl), C₁₋₄haloalkyl (e.g., —CF₃, —CH₂CF₃), halogen (e.g., fluoro), and oxo. In one embodiment, G⁴ is

each being optionally substituted with one C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, or oxo. In some embodiments, R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl and X¹, X², and X³ are as defined herein. In other embodiments, G⁴ is

Included in compounds of formula (III′) are compounds of formula (IIIA′) to (IIIG′), wherein G¹, G², G³, G⁴, G⁵, G⁶, R², R⁴, R⁶, R⁷, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIIA′) to (IIIG′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIIA′), are compounds of formula (IIIA-1′) and (IIIA-2′), wherein s, G¹, R², R⁴, R^(8′), X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIIA-1′) and (IIIA-2′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (IIIA-1′) and (IIIA-2′) may be represented by the formulas (IIIA-1.0′), (IIIA-1.1′), (IIIA-1.2′), or (IIIA-2.0′):

wherein R², R⁴, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIIA-1.0′), (IIIA-1.1′), (IIIA-1.2′), and (IIIA-2.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIIC′), are compounds of formula (IIIC-1′) to (IIIC-6′), wherein R¹² represents the optional G² substitution, as defined herein, n is an integer from 0-4, and R², R⁴, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIIC-1′) to (IIIC-6′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, R¹² is —C₁₋₄alkylene-OC₁₋₄alkyl or —C(O)C₁₋₄alkyl and n is 1. In a subgroup of compounds, n is 1 and R¹² is —C₁₋₄alkylene-OC₁₋₄alkyl or —C(O)C₁₋₄alkyl and is bonded to an available ring nitrogen atom. In compounds of formulas (IIIC-1′) to (IIIC-6′),

and are as defined elsewhere herein.

In some embodiments of formula (IIIC-3′), (IIIC-5′), and (IIIC-6′) are compounds of formula (IIIC-3.0′), (IIIC-5.0′), and (IIIC-6.0′), wherein R^(12A) is H or R¹², and R², R⁴, R¹², X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIIC-3.0′), (IIIC-5.0′), and (IIIC-6.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIIF′), are compounds of formula (IIIF-1′) and (IIIF-2′), wherein R¹⁴ is the optional substituent on G⁵, p is an integer from 0-4, and R², R⁴, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IIIF-1′) and (IIIF-2′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IIIF-2′) are compounds of formula (IIIF-2.0′), wherein R^(14A) is H or R¹⁴. In some groups of compounds R^(14A) is —NHC(O)(C₁₋₄alkyl).

In some embodiments, the present invention features compounds of formula (IIIF-2.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

Included in compounds of formula (IV′) are compounds of formula (IVA′) to (IVH′) and (IVJ′), wherein L², G¹, G², G³, G⁴, G⁵, G⁶, R², R⁴, R⁵, R⁶, R⁷, X¹, X², and X³ are as defined herein:

In some embodiments, the present invention features compounds of formulas (IVA′) to (IVH′) and (IVJ′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (IVA′), are compounds of formula (IVA-1′) and (IVA-2′), wherein s, G¹, R², R⁴, R⁵, R^(8′), X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IVA-1′) and (IVA-2′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (IVA-1′) and (IVA-2′) may be represented by the formulas (IVA-1.0′) to (IVA-2.0′).

In some embodiments, the present invention features compounds of formulas (IVA-1.0′) to (IVA-2.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formulas (IVA′) to (IVG′), (IVA-1′), (IVA-2′), (IVA-1.0′), (IVA-1.1′), or (IVA-2.0′), R⁵ is H or methyl;

In some embodiments of formula (IVC′), are compounds of formula (IVC-1′) to (IVC-6′), wherein n, R², R⁴, R⁵, R¹², X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IVC-1′) to (IVC-6′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, R¹² is —C₁₋₄alkylene-OC₁₋₄alkyl, —C(O)C₁₋₄alkyl, or C₁₋₄alkyl and n is 1. In a subgroup of compounds, n is 1 and R¹² is —C₁₋₄alkylene-OC₁₋₄alkyl or —C(O)C₁₋₄alkyl and is bonded to an available ring nitrogen atom. In compounds of formulas (IVC-1′) to (IVC-6′),

and are as defined herein.

In some embodiments, compounds of formula (IVC-1′) (IVC-3′), (IVC-4′), (IVC-5′), and (IVC-6′) may be represented by the formulas (IVC-1.0′), (IVC-3.0′), (IVC-3.1′), (IVC-4.0′), (IVC-5.0′), and (IVC-6.0′), wherein R^(12A) and R^(12B) are independently H or R¹², and R², R⁴, R⁵, R¹², X¹, X², and X³ are as defined herein. In some embodiments, R^(12A) is —C₁₋₄alkylene-OC₁₋₄alkyl, or —C(O)C₁₋₄alkyl. In some embodiments, R^(12B) is H or C₁₋₄alkyl.

In some embodiments, the present invention features compounds of formulas (IVC-1′) to (IVC-6′), (IV-1.0′), (IVA-3.0′), (IVC-3.1′), (IVC-4.0′), (IVC-5.0′), and (IVC-6.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formulas (IVC-1′) to (IVC-6′), (IV-1.0′), (IVA-3.0′), (IVC-3.1′), (IVC-4.0′), (IVC-5.0′), or (IVC-6.0′), R⁵ is H or methyl;

In some embodiments of formula (IVF′), are compounds of formula (IVF-1′) and (IVF-2′), wherein R¹⁴ is the optional substituent on G⁵, p is an integer from 0-4, and R², R⁴, R⁵, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IVF-1′) and (IVF-2′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (IVF-1′) and (IVF-2′) may be represented by the formulas (IVF-1.0′) and (IVF-2.0′).

In some embodiments, the present invention features compounds of formulas (IVF-1.0′) and (IVF-2.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formulas (IVF-1′), (IVF-2′), (IVF-1.0′) or (IVF-2.0′), R⁵ is H or methyl.

In some embodiments of formula (IVG′), are compounds of formula (IVG-1′) to (IVG-4′), wherein R¹⁵ is the optional substituent on G⁶, t is an integer from 0-4, and R², R⁴, R⁵, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (IVG-1′) to (IVG-4′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (IVG-1′)-(IVG-4′) may be represented by the formulas (IVG-1.0′)-(IVG-4.0′), where R^(15A) is H or R¹⁵. In some embodiments, R^(15A) is H, phenyl or C₁₋₄alkyl.

In some embodiments, the present invention features compounds of formulas (IVG-1.0′) to (IVG-4.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formulas (IVH′) and (IVJ′), are compounds, respectively, of formulas (IVH-1′) and (IVJ-1′), wherein G¹, R², R⁴, R⁵, R⁶, R⁷, X¹, X², and X³ are as defined herein and wherein one or more hydrogen atoms are optionally replaced by a deuterium atom.

Included in compounds of formula (V′) are compounds of formula (VA′), (VB′), (VC′), (VD′), (VE′), (VF′), (VG′), or (VH′), wherein —NR⁵—C₁₋₄alkylene-, G¹, G², G³, G⁴, G⁵, G⁶, G⁷, R², R⁴, R⁶, R⁷, X¹, X², and X³ are as defined herein:

In some embodiments, the present invention features compounds of formulas (VA′), (VB′), (VC′), (VD′), (VE′), (VF′), (VG′), and (VH′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (VA′), are compounds wherein G¹ is a 3-8 membered cycloalkyl optionally substituted as described herein. In subsets of these compounds, R⁶ is the 4- to 8-membered monocyclic heterocyclic ring as described herein. In further subsets of compounds, the C₁₋₄alkylene is a methylene. In further subsets of compounds, R⁶ is the 4- to 8-membered monocyclic heterocyclic ring as described herein and the C₁₋₄alkylene is a methylene.

In some embodiments of formula (VA′), are compounds wherein G¹ is a 4- to 8-membered monocyclic heterocyclic ring as described herein (e.g., oxetanyl, piperidinyl). In subsets of these compounds, R⁶ is the 4- to 8-membered monocyclic heterocyclic ring as described herein (e.g., pyrrolidinyl, tetrahydropyranyl). In further subsets of compounds, the C₁₋₄alkylene is a methylene. In further subsets of compounds, R⁶ is the 4- to 8-membered monocyclic heterocyclic ring as described herein and the C₁₋₄alkylene is a methylene. Representative examples include the Compound numbers 1020 and 1046.

In some embodiments of formula (VB′), are compounds wherein G¹ is a 4- to 8-membered monocyclic heterocyclic ring as described herein (e.g., morpholino). In subsets of these compounds, R⁷ is a 3-8 membered cycloalkyl optionally substituted as described herein (e.g., cyclopropyl). In further subsets of compounds, the C₁₋₄alkylene is a methylene. In further subsets of compounds, R⁷ is a 3-8 membered cycloalkyl optionally substituted as described herein and the C₁₋₄alkylene is a methylene. A representative example includes Compound number 968.

In some embodiments of formula (VC′), are compounds of formula (VC-1′) and (VC-2′) wherein

n, —NR⁵—C₁₋₄alkylene-, R², R⁴, R¹², X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (VC-1′) and (VC-2′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (VC-1′) and (VC-2′) may be represented by the formula (VC-1.0′) and (VC-2.0′), where R^(12B) is H or R¹². In some embodiments, R^(12B) is H or C₁₋₄alkyl (e.g., methyl) and the C₁₋₄alkylene is methylene, ethylene, or propylene, optionally substituted with 1-3 fluoros.

In some embodiments, the present invention features compounds of formulas (VC-1.0′) and (VC-2.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In other embodiments of formula VC′ are compounds where G² is an azetidinyl, 1,4-dioxanyl, or 4,5-dihydroisoxazolyl (i.e., isoxazoline), for example, as shown in Compound numbers 932, 1004 or 1084.

In some embodiments of formulas (VA′) to (VH′), (VC-1′), (VC-2′), (VC-1.0′), or (VC-2.0′), R⁵ is H or methyl.

Included in compounds of formula (VI′) are compounds of formula (VIA′), (VIB′), (VIC′), (VID′), (VIE′), (VIF′), or (VIG′), wherein G¹, G², G³, G⁴, G⁵, G⁶, R⁴, R⁶, R⁷, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (VIA′), (VIB′), (VIC′), (VID′), (VIE′), (VIF′), and (VIG′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (VIC′), are compounds of formula (VIC-1′) to (VIC-4′), wherein

n, R², R⁴, R¹², X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (VIC-1′) to (VIC-4′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (VIC-1′), (VIC-2′), (VIC-3′), and (VIC-4′) may be represented by the formulas (VIC-1.0′)-(VIC-4.0′), wherein R^(12B) is H or R¹². In some embodiments, R^(12B) is H or C₁₋₄alkyl (e.g., methyl) and the C₁₋₄alkylene is methylene or ethylene.

In some embodiments, the present invention features compounds of formulas (VIC-1.0′) to (VIC-4.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (VIF′), are compounds of formula (VIF-1′), wherein p, R², R⁴, R¹⁴, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formula (VIF-1′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (VIF-1′) may be represented by the formulas (VIF-1.0′), wherein R^(14A) is H or R¹⁴. For example, in some cases R^(14A) is halogen (e.g., fluoro).

In some embodiments, the present invention features compounds of formula (VIF-1.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (VIG′), are compounds of formula (VIG-1′) and (VIG-2′), wherein R¹⁵ is the optional substituent on G⁶, t is an integer from 0-4, and R², R⁴, R⁵, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (VIG-1′) and (VIG-2′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (VIG-1′) may be represented by the formulas (VIG-1.0′), where R^(15A) is H or R¹⁵. In some embodiments, R^(15A) is phenyl or C₁₋₄alkyl.

In some embodiments, the present invention features compounds of formula (VIG-1.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

Included in compounds of formula (VII′) are compounds of formula (VIIA′) to (VIIG′), wherein G¹, G², G³, G⁴, G⁵, G⁶, R², R⁴, R⁶, R⁷, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (VIIA′) to (VIIG′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (VIIA′), are compounds of formula (VIIA-1′), wherein s, G¹, R², R⁴, R^(8′), X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formula (VIIA-1′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (VIIA-1′) may be represented by the formula (VIIA-1.0′) or (VIIA-2.0′). As shown in (VIIA-2.0′), in some embodiments, the C₁₋₄alkylene is a CH₂ group.

In some embodiments, the present invention features compounds of formulas (VIIA-1.0′) and (VIIA-2.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

Included in compounds of formula (VIII′) are compounds of formula (VIIIA′) to (VIIIG′), wherein G¹, G², G³, G⁴, G⁵, G⁶, R², R⁴, R⁶, R⁷, X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formulas (VIIIA′) to (VIIIG′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments of formula (VIIIA′), are compounds of formula (VIIA-1′), wherein s, G¹, R², R⁴, R^(8′), X¹, X², and X³ are as defined herein.

In some embodiments, the present invention features compounds of formula (VIIIA-1′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In some embodiments, compounds of formula (VIIIA-1′) may be represented by the formula (VIIIA-1.0′).

In some embodiments, the present invention features compounds of formula (VIIIA-1.0′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In each of the foregoing embodiments related to compounds of formulas (II′) to (VIII′), and associated subformulas and compounds, are embodiments wherein R² is C₁₋₄alkyl C₁₋₄haloalkyl, or C₃₋₆cycloalkyl; R⁴ is phenyl optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl or R⁴ is pyrazinyl. In some embodiments, R² is methyl, ethyl, trifluoromethyl, difluoromethyl, or cyclopropyl; and R⁴ is phenyl, 3,5-difluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3-fluoro-5-methylphenyl, or pyrazin-2-yl. In further embodiments, X¹, X², and X³ are each CH. In other embodiments, X¹ is CH, X² is CR^(X2), and X³ is CR³. In other embodiments, X¹ is CH, X² is CR^(X2), and X³ is CH. In other embodiments, X¹ is CH, X² is C—F, and X³ is CH. In other embodiments, X¹ is CH, X² is CH, and X³ is CR³. In other embodiments, X¹ is N and X² and X³ and are CH. In other embodiments, X¹ is N, X² is CR^(X2), and X³ is CR³. In other embodiments, X¹ is CH, X² is N, and X³ is CH. In other embodiments, X¹ is CH, X² is N, and X³ is CR³. In other embodiments, X¹ and X² are CH, and X³ is N. In other embodiments, X¹ is CH, X² is CR^(X2), and X³ is N. In other embodiments, X¹ and X² are N, and X³ is CH. In other embodiments, X¹ and X² are N, and X³ is CR³.

In some embodiments according to formulas (II′) to (VIII′), and associated subformulas and compounds are further compounds where X¹ is H, X³ is H, X² is CR^(X2) and R^(X2) is hydrogen or fluoro. In other embodiments, R^(X2) is fluoro. For example, in some embodiments are compounds of formula (X′), wherein R¹, R², R⁴, and L¹ are as defined in the description and embodiments herein.

In some embodiments, the present invention features compounds of formula (X′) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In another embodiment, the compounds of formula I or I′ include isotope-labelled forms thereof. An isotope-labelled form of a compound of formula I or I′ is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs in greater natural abundance. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of formula I or I′ by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively.

In another embodiment, a compound of formula I or I′ or a pharmaceutically acceptable salt thereof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.

In another embodiment, the present invention features a compound of formula I or I′ and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

In another embodiment, an isotope-labelled compound of formula I or I′ can be used in a number of beneficial ways. In one embodiment, an isotope-labelled compound of formula I or I′ into which, for example, a radioisotope, such as ³H or ¹⁴C, has been incorporated is suitable for a medicament and/or for substrate tissue distribution assays. In one embodiment, tritium (³H) and carbon-14 (¹⁴C) are particularly preferred owing to simple preparation and excellent detectability.

In yet another embodiment, incorporation of heavier isotopes, for example deuterium (²H), into a compound of formula I or I′ have therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of formula I or I′ can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

In another embodiment, Deuterium (²H) can also be incorporated into a compound of formula I or I′ for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of k_(M/kD)=2-7 are typical. If this rate difference is successfully applied to a compound of formula I or I′ that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference.

When discovering and developing therapeutic agents, the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of formula I or I′ with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of compounds of formula I or I′ are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (t_(1/2)), concentration at maximum therapeutic effect (C_(max)), area under the dose response curve (AUC), and bioavailability; and in terms of reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of formula I or I′ which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.

In another embodiment, deuterium-hydrogen exchange in a compound of formula I or I′ can be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

In another embodiment, the invention features a compound of formula I or I′, wherein the compound or a pharmaceutically acceptable salt thereof, is selected from Table 1 below. In the Table 1 below, compounds 92 and 473 are each single enantiomers with unknown stereochemistry and are arbitrarily assigned the “S” and “R” conformation, respectively. Compounds 101 and 487 are also each single enantiomers with unknown stereochemistry and are arbitrarily assigned the “S” and “R” conformation, respectively. Compound 208 is a racemic mixture of the (S,R) and (R,R) diastereomers where the stereocenters are in a cis configuration. Compound 282 is a racemic mixture of the (R,R) and (S,S) diastereomers where the stereocenters are in a trans configuration.

TABLE 1 Compound Table

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

In Table 1A below, several compounds have stereocenters with either known (R or S) or unknown absolute configurations and/or known (cis or trans) or unknown configurations. For example, compounds 603, 611, 623, 632, 655, 665, 667, 672, 673, 679, 682, 696, 700, 740, 748, 750, 751, 787, 796 and 800 are each single enantiomers with unknown stereochemistry and are arbitrarily assigned the “S” or “R” conformation. Compounds 649 and 792 are each single enantiomers of unknown cis/trans configuration and are arbitrarily assigned a trans conformation. Compounds 826 and 861 are each single enantiomers of unknown cis/trans configuration and are arbitrarily assigned a cis conformation.

TABLE 1A Compound Table

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

In Table 1B below, several compounds have stereocenters with either known (R or S) or unknown absolutely configurations and/or known (cis or trans) or unknown configurations. For example, compound 919 is a single enantiomer with the “S” conformation. Compounds 886, 1002, 1009, 1028, 1052, 1053, 1055, and 1061 are each single enantiomers with unknown stereochemistry and are arbitrarily assigned the “S” or “R” conformation.

TABLE 1B Compound Table

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

995

996

997

998

999

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

1071

1072

1073

1074

1075

1076

1077

1078

1079

1080

1081

1082

1083

1084

1085

1086

1087

1088

1089

1090

1091

1092

1093

1094

1095

1096

1097

1098

1099

1100

1101

1102

1103

1104

1105

1106

1107

1108

1109

1110

1111

1112

1113

1114

1115

1116

1117

1118

1119

1120

1121

1122

1123

TABLE 2 Compound Names (IUPAC Nomenclature) Cmpd Number IUPAC Name 1 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-4-amine 2 1-(3,5-difluorophenyl)-N-[3-(3-methoxyazetidin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 3 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- (3,6-dihydro-2H-pyran-4-yl)pyridin-4-amine 4 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-2-yl]cyclobutanol 5 N-[3-chloro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 6 3-methyl-1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]pyrrolidin-3-ol 7 N-[3-methyl-5-(6-oxa-2-azaspiro[3.3]heptan-2-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 8 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- tetrahydrofuran-3-yl-benzene-1,3-diamine 9 2-cyclopropyl-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-N-(1- phenyl-1,2,4-triazol-3-yl)pyridin-4-amine 10 N-[3,5-di(tetrahydropyran-4-yl)phenyl]-1-phenyl-1,2,4-triazol- 3-amine 11 N-[3-methyl-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 12 methyl 4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-1-carboxylate 13 N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1- (4-pyridyl)-1,2,4-triazol-3-amine 14 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- fluorophenyl)-1,2,4-triazol-3-amine 15 N-[3-ethyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 16 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 17 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 18 N-[3-[3-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl]-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine 19 1-(3,5-difluorophenyl)-N-[3-(6,8-dihydro-5H-imidazo[1,2- a]pyrazin-7-yl)-5-methyl-phenyl]-1,2,4-triazol-3-amine 20 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 21 N-[3-(2,5-dimethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 22 2-cyclopropyl-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-(4-methyl-1-piperidyl)pyridin-4-amine 23 1-(3,5-difluorophenyl)-N-[3-(3-fluoro-1-methyl-pyrrolidin-3- yl)-5-methyl-phenyl]-1,2,4-triazol-3-amine 24 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 25 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 26 N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 27 1-(3-fluorophenyl)-N-(3-methyl-5-morpholino-phenyl)-1,2,4- triazol-3-amine 28 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(4-methyl-1,4-diazepan- 1-yl)phenyl]-1,2,4-triazol-3-amine 29 N-[3-[(8aR)-4-isobutyl-3,4,6,7,8,8a-hexahydro-1H- pyrrolo[1,2-a]pyrazin-2-yl]-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 30 1-(2-methoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 31 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(p- tolyl)-1,2,4-triazol-3-amine 32 1-(3-chloro-5-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 33 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 34 1-(3,5-difluorophenyl)-N-[3-methyl-S-[(1S,4S)-2-(oxetan-3- yl)-2,5-diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3- amine 35 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- (3,6-dihydro-2H-pyran-4-yl)pyridin-4-amine 36 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)azetidin-3- yl]phenyl]-1,2,4-triazol-3-amine 37 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 38 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 39 N-(3-methyl-5-pyrrolidin-3-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine 40 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 41 1-[3-[2-(ethoxymethyl)pyrrolidin-1-yl]-5-fluoro-phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 42 1-(2-chloro-4-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 43 1-(3,4-difluorophenyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 44 2-cyclopropyl-6-(4-methyl-1-piperidyl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-4-amine 45 N-(3-methyl-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 46 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 47 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 48 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 49 N-(3-fluoro-5-morpholino-phenyl)-1-(2-fluorophenyl)-1,2,4- triazol-3-amine 50 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(5- fluoropyrimidin-4-yl)-1,2,4-triazol-3-amine 51 N-[3-[1-[3-(benzenesulfonylmethyl)oxetan-3-yl]-4-piperidyl]- 5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 52 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 53 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-piperazin-2-yl]methanol 54 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- methyl-2-pyridyl)-1,2,4-triazol-3-amine 55 1-(3-chlorophenyl)-N-[3-cyclopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 56 1-(3-fluoro-5-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 57 (2R)-3-methyl-2-[4-[6-methyl-4-[(1-phenyl-1,2,4-triazol-3- yl)amino]-2-pyridyl]piperazin-2-yl]butan-2-ol 58 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 59 [4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-yl]methanol 60 N-[3-methyl-5-(1-methyl-3-piperidyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 61 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3,6- dihydro-2H-pyridin-4-yl]phenyl]-1,2,4-triazol-3-amine 62 N-[3-(difluoromethyl)-5-piperazin-1-yl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 63 1-(3,5-difluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 64 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylsulfanylpyrimidin-4-yl)-1,2,4-triazol-3-amine 65 N-[3-methyl-5-[1-(oxetan-3-yl)azetidin-3-yl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 66 2,5-difluoro-4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]benzonitrile 67 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-(oxetan-3-yl)piperazin-2-one 68 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyrazin-2- yl-1,2,4-triazol-3-amine 69 1-(3,4-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 70 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(p- tolyl)-1,2,4-triazol-3-amine 71 N-[3-methyl-5-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 72 ethyl 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]acetate 73 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluoro-5-methyl-phenyl)-1,2,4-triazol-3-amine 74 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-pyrazin- 2-yl-1,2,4-triazol-3-amine 75 N-[3-[4-(3,3-difluorocyclobutyl)piperazin-1-yl]-5-methyl- phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 76 1-methyl-4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-one 77 1-(3,5-difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)- 1,2,4-triazol-3-amine 78 N-[3-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5- yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 79 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propane-1,3-diol 80 N-(3-fluoro-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 81 4-[3-[3-methyl-5-(4-methylpiperazin-1-yl)anilino]-1,2,4- triazol-1-yl]benzonitrile 82 N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 83 1-(2-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 84 N-(3-methyl-5-morpholino-phenyl)-1-(4-pyridyl)-1,2,4-triazol- 3-amine 85 N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-(2-fluoro-4- pyridyl)-1,2,4-triazol-3-amine 86 1-(3-methoxyphenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 87 N-[3-(4-cyclopentylpiperazin-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 88 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 89 N-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 90 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]ethanone 91 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 92 1-(3,5-difluorophenyl)-N-[3-methyl-S-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 93 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-2-one 94 1-(3-methoxyphenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 95 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(thietan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 96 N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 97 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 98 N-[3-fluoro-5-(4-methyl-1,4-diazepan-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 99 1-(3,4-difluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 100 2-chloro-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 101 (3S)-3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 102 1-(4-fluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 103 1-[3-(2-ethylpyrrolidin-1-yl)-5-fluoro-phenyl]-N-[3-methyl-5- [4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 104 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 105 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 106 2-chloro-N-[1-(3-methoxyphenyl)-1,2,4-triazol-3-yl]-6-(1- piperidyl)pyridin-4-amine 107 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 108 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-piperidyl)phenyl]- 1,2,4-triazol-3-amine 109 N-[3-[3-(dimethylamino)pyrrolidin-1-yl]-5-fluoro-phenyl]-1- (3-fluorophenyl)-1,2,4-triazol-3-amine 110 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine 111 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 112 1-(3,5-difluorophenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 113 N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 114 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-piperidyl]pyrrolidin-2-one 115 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]anilino]- 1-piperidyl]ethanone 116 1-(3,5-difluorophenyl)-N-[3-[3-(methoxymethyl)azetidin-1- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 117 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 1-piperidyl]ethanone 118 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 119 1-(3,5-difluorophenyl)-N-[3-(3,4-dimethylpiperazin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 120 N-[3-(1-cyclopropyl-4-piperidyl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 121 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,6-difluoro-4-pyridyl)-1,2,4-triazol-3-amine 122 1-(2-fluoro-4-pyridyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 123 2-[(2S)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-(trifluoromethyl)phenyl]piperazin-2-yl]propan-2- ol 124 N-(3-ethyl-5-piperazin-1-yl-phenyl)-1-pyrazin-2-yl-1,2,4- triazol-3-amine 125 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]aceticacid 127 N-[3-methyl-5-[4-(2-methyltetrahydrofuran-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 128 N-[3-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin- 2-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 129 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,6-dimethylpyrimidin-4-yl)-1,2,4-triazol-3-amine 130 1-(3,5-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 131 1-(3,5-difluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine 132 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylsulfanylpyrimidin-4-yl)-1,2,4-triazol-3-amine 133 N-[3-(3,4-dimethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 134 1-(5-chloro-3-pyridyl)-N-[3-cyclopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 135 2-chloro-6-morpholino-N-(1-phenyl-1,2,4-triazol-3-yl)pyridin- 4-amine 136 N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1- yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 137 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydrofuran-3- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 138 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-(2-pyridyl)- 1,2,4-triazol-3-amine 139 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-4- oxido-piperazin-4-ium-1-yl]phenyl]-1,2,4-triazol-3-amine 140 2-fluoro-4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]benzonitrile 141 1-(3-chlorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 142 1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-4-carbonitrile 143 methyl 3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-1-carboxylate 144 1-[4-[3-(difluoromethyl)-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]ethanone 145 2-chloro-N-[1-(3-methoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 146 1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-3-carbonitrile 147 1-(3-fluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]-1,2,4- triazol-3-amine 148 N-[3-[4-(2-methoxyethyl)-1-piperidyl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 149 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 150 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- tetrahydropyran-4-yl-pyridin-4-amine 151 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-methyl-4- piperidyl)phenyl]-1,2,4-triazol-3-amine 152 N-[3-[(8aR)-4-isobutyl-3,4,6,7,8,8a-hexahydro-1H- pyrrolo[1,2-a]pyrazin-2-yl]-5-methyl-phenyl]-1-phenyl-1,2,4- triazol-3-amine 153 N-[3-(4-cyclopropylpiperazin-1-yl)-5- (difluoromethyl)phenyl]-1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3- amine 154 1-(6-fluoro-2-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 155 4-[3-(3-methyl-5-morpholino-anilino)-1,2,4-triazol-1- yl]pyridin-2-ol 156 2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-4-amine 157 N-[3-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin- 2-yl]-5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 158 N-(3-fluoro-5-morpholino-phenyl)-1-(3-fluorophenyl)-1,2,4- triazol-3-amine 159 N-(3-methyl-5-piperazin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine 160 N-[3-methyl-5-[1-(oxetan-3-yl)-2,5-dihydropyrrol-3- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 161 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]pyrrolidin-2-one 162 1-(3,5-difluorophenyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 163 4-[3-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]-1H-pyridin-2-one 164 1-(3,5-difluorophenyl)-N-[3-(3-methoxypyrrolidin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 165 N-(3-morpholino-5-tetrahydrofuran-3-yl-phenyl)-1-phenyl- 1,2,4-triazol-3-amine 166 N-[3-fluoro-5-(1,4-oxazepan-4-yl)phenyl]-1-(3-fluorophenyl)- 1,2,4-triazol-3-amine 167 1-(4-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 168 N-(3-bromo-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 169 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 170 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- pyrrolidin-1-yl-pyridin-4-amine 171 1-(3,5-difluorophenyl)-N-[3-methyl-5-(6-oxa-2- azaspiro[3.3]heptan-2-yl)phenyl]-1,2,4-triazol-3-amine 172 N-[3-methyl-5-(4-tetrahydropyran-3-ylpiperazin-1-yl)phenyl]- 1-phenyl-1,2,4-triazol-3-amine 173 1-(3,5-difluorophenyl)-N-[3-ethyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 174 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 175 1-(3-fluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 176 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 177 N1-(azetidin-3-yl)-N3-[1-(2,4-difluorophenyl)-1,2,4-triazol-3- yl]-5-fluoro-benzene-1,3-diamine 178 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 179 N-[3-methyl-5-(4-methyl-1,4-diazepan-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 180 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 181 N-(3-fluoro-5-morpholino-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 182 N1-[1-(3-methoxypropyl)-4-piperidyl]-5-methyl-N3-(1- phenyl-1,2,4-triazol-3-yl)benzene-1,3-diamine 183 1-(3,4-difluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 184 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-fluoro-4-pyridyl)-1,2,4-triazol-3-amine 185 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-2-(oxetan-3- yl)-2,5-diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3- amine 186 4-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile 187 1-[3-[[ethyl(methyl)amino]methyl]-5-fluoro-phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 188 N3-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 189 N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-amine 190 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 191 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 192 N3-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 193 1-(3,5-difluorophenyl)-N-[3-[3-fluoro-1-(oxetan-3- yl)pyrrolidin-3-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 194 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 1-piperidyl]ethanone 195 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 196 ethyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazine-1-carboxylate 197 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1,5-dimethyl- N1-(oxetan-3-yl)benzene-1,3-diamine 198 1-(3,4-difluorophenyl)-N-[3-ethyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 199 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydropyran-3- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 200 7-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin- 3-one 201 1-(4-fluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 202 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- (4-methyl-1-piperidyl)pyridin-4-amine 203 N-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 204 1-(2-ethoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 205 1-(3-fluoro-5-isopropoxy-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 206 1-(3-ethyl-5-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 207 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 208 1-(3,5-difluorophenyl)-N-[3-[(3S,4R)-3-fluoro-1-(oxetan-3- yl)-4-piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine; 1- (3,5-difluorophenyl)-N-[3-[(3R,4S)-3-fluoro-1-(oxetan-3-yl)- 4-piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 209 N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 210 2-cyclopropyl-N-[1-(3,5-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-morpholino-pyridin-4-amine 211 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 212 2-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile 213 N-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 214 1-cyclopropyl-4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-one 215 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 216 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 217 1-(5-chloro-3-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 218 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 219 N-[3-methyl-5-[(1S,4S)-2-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1-phenyl-1,2,4-triazol- 3-amine 220 1-(3-chloro-5-fluoro-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 221 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-4- piperidyl]phenyl]-1,2,4-triazol-3-amine 222 2-cyclopropyl-6-morpholino-N-(1-phenyl-1,2,4-triazol-3- yl)pyridin-4-amine 223 1-(2-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 224 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- pyridyl)-1,2,4-triazol-3-amine 225 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-fluorophenyl)-1,2,4-triazol-3-amine 226 1-(2-fluoro-4-pyridyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 227 7-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3-one 228 1-(3,5-difluorophenyl)-N-[3-[4-(1,1-dioxothietan-3- yl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 229 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)azetidin-3-yl]phenyl]-1,2,4-triazol-3-amine 230 N-[3-fluoro-5-[1-(oxetan-3-yl)pyrrolidin-3-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 231 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 232 1-(2,6-difluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 233 1-[2-(methoxymethyl)phenyl]-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 234 N-[3,5-bis(2,5-dihydrofuran-3-yl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 235 N-[3-[3,3-difluoro-1-(oxetan-3-yl)-4-piperidyl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 236 N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5-propyl-phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 237 N-[2,3-dimethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 238 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperidin-4-ol 239 N-[3-methyl-5-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy- phenyl]-1-phenyl-1,2,4-triazol-3-amine 240 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (oxetan-3-yl)benzene-1,3-diamine 241 N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 242 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-pyrrolidin-3-ol 243 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydropyran-4- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 244 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- (4-methyl-1-piperidyl)pyridin-4-amine 245 2-cyclopropyl-N-[1-(3,5-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-[(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 246 N-[3-chloro-5-[4-(methoxymethyl)-1-piperidyl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 247 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 248 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 249 N3-[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 250 N-[3,5-di(tetrahydropyran-4-yl)phenyl]-1-(3-pyridyl)-1,2,4- triazol-3-amine 251 N-(3-morpholino-5-tetrahydropyran-4-yl-phenyl)-1-phenyl- 1,2,4-triazol-3-amine 252 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine 253 N-[3-[4-(2-methoxyethyl)piperazin-1-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 254 1-(6-methoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 255 1-(3-ethyl-5-fluoro-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 257 1-(3-fluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 258 1-(3-fluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 259 N-[3-methyl-5-(3-methylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 260 N-[3-methyl-5-[1-(oxetan-3-yl)pyrrolidin-3-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 261 N-[3-(1-cyclopropyl-4-piperidyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 262 1-(5-chloro-3-pyridyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 263 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-(4- methylpiperazin-1-yl)pyridin-4-amine 264 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 265 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6- morpholino-pyridin-4-amine 266 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]ethanone 267 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (methylamino)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine 268 1-(3,5-difluorophenyl)-N-[3-fluoro-5-[1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 269 1-(4-fluorophenyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 270 N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-(3-pyridyl)-1,2,4- triazol-3-amine 271 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 272 1-(3-fluorophenyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 273 N-[3-[1-(2,2-difluoroethyl)pyrrolidin-3-yl]-5-methyl-phenyl]- 1-phenyl-1,2,4-triazol-3-amine 274 N-[3-(4-ethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl-1,2,4- triazol-3-amine 275 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- pyridyl)-1,2,4-triazol-3-amine 276 1-(2,3-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 277 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 278 N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 279 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-7- azaspiro[3.5]nonan-7-yl)phenyl]-1,2,4-triazol-3-amine 280 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 1,4-diazepan-1-yl]ethanone 281 3-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile 282 (3R,4R)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-1-(oxetan-3-yl)piperidin-3-ol; (3S,4S)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-1-(oxetan-3-yl)piperidin-3-ol 283 N-[3-(3-aminoazetidin-1-yl)-5-fluoro-phenyl]-1-(2,4- difluorophenyl)-1,2,4-triazol-3-amine 284 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3- morpholinopyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 285 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluoro-5-isopropoxy-phenyl)-1,2,4-triazol-3-amine 286 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-ethoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 287 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 288 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 289 N-[3-methyl-5-(4-tetrahydropyran-4-ylpiperazin-1-yl)phenyl]- 1-phenyl-1,2,4-triazol-3-amine 290 N-[3-(4-cyclobutylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 291 1-(5-fluoropyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 292 N-[3-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5- yl]-5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 293 1-(3,5-difluorophenyl)-N-[3-(3-methoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 294 N-[3-methyl-5-[1-(3-methyloxetan-3-yl)-4-piperidyl]phenyl]- 1-phenyl-1,2,4-triazol-3-amine 295 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]oxazolidin-2-one 296 2-cyclopropyl-6-[(3R)-3-fluoropyrrolidin-1-yl]-N-(1-phenyl- 1,2,4-triazol-3-yl)pyridin-4-amine 297 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-(3-pyridyl)- 1,2,4-triazol-3-amine 298 1-(3,5-difluorophenyl)-N-[3-(2,5-dihydrofuran-3-yl)-5- morpholino-phenyl]-1,2,4-triazol-3-amine 299 1-(3,4-difluorophenyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 300 1-[3-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]-1-piperidyl]ethanone 301 1-(3,4-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)azetidin-3-yl]phenyl]-1,2,4-triazol-3-amine 302 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (6-methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 303 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine 304 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 305 N-(3-cyclopropyl-5-morpholino-phenyl)-1-phenyl-1,2,4- triazol-3-amine 306 N-[3-(2,6-dimethylmorpholin-4-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 307 N-(2-fluoro-3-methyl-5-morpholino-phenyl)-1-(2-pyridyl)- 1,2,4-triazol-3-amine 308 N-[3-methyl-5-(4-piperidyl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 309 5-methyl-N1-[1-(oxetan-3-yl)pyrrolidin-3-yl]-N3-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 310 1-(3,5-difluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 311 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2-methyl-propane-1,3-diol 312 1-(2,6-dimethylpyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 313 1-(3,5-difluorophenyl)-N-[3-(oxetan-3-yl)-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 314 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 315 N-[3,5-bis(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 316 N-[3-methyl-5-(3-piperidyl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 317 1-(3,4-difluorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 318 2-[(3R)-1-[3-fluoro-S-[3-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]anilino]-1,2,4-triazol-1-yl]phenyl]pyrrolidin- 3-yl]propan-2-ol 319 2,6-dimorpholino-N-(1-phenyl-1,2,4-triazol-3-yl)pyridin-4- amine 320 1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 321 1-(2,4-difluorophenyl)-N-(3-fluoro-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 322 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 323 1-(3-fluoro-5-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 324 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-morpholino-1- piperidyl)phenyl]-1,2,4-triazol-3-amine 325 1-(3,5-difluorophenyl)-N-[3-[2-(methoxymethyl)morpholin-4- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 326 N-[3-(4-isopropylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 327 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- (1-piperidyl)pyridin-4-amine 328 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-methyl-3- piperidyl)phenyl]-1,2,4-triazol-3-amine 329 1-(4,6-difluoro-2-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 330 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 331 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 332 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3S)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 333 N-[3-methyl-5-(1-methyl-4-piperidyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 334 5-methyl-N1-[1-(oxetan-3-yl)-4-piperidyl]-N3-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 335 N-(3-chloro-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 336 N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine 337 N-[3-(4-cyclopropyl-1,4-diazepan-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 338 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-5-methyl-phenyl)-1,2,4-triazol-3-amine 339 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (5-fluoro-3-pyridyl)-1,2,4-triazol-3-amine 340 N-[3-(1-cyclopropyl-3-piperidyl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 341 N-[3-ethyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-pyrazin-2- yl-1,2,4-triazol-3-amine 342 5-methyl-N1-[1-(oxetan-3-yl)-4-piperidyl]-N3-[1-(3-pyridyl)- 1,2,4-triazol-3-yl]benzene-1,3-diamine 343 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(1,4-oxazepan-4- yl)phenyl]-1,2,4-triazol-3-amine 344 1-(3,5-difluorophenyl)-N-[3-methylsulfonyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 345 2-chloro-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 346 N-(3-bromo-5-morpholino-phenyl)-1-(3,5-difluorophenyl)- 1,2,4-triazol-3-amine 347 1-(2,4-difluorophenyl)-N-[3-[3-(dimethylamino)pyrrolidin-1- yl]-5-fluoro-phenyl]-1,2,4-triazol-3-amine 348 N-[3-(4-cyclopropylpiperazin-1-yl)-5- (difluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine 349 1-(3,5-difluorophenyl)-N-[3-methyl-5-(9-methyl-2-oxa-6,9- diazaspiro[3.5]nonan-6-yl)phenyl]-1,2,4-triazol-3-amine 350 2,2,2-trifluoroethyl4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate 351 N1-(azetidin-3-yl)-5-fluoro-N3-[1-(3-fluorophenyl)-1,2,4- triazol-3-yl]benzene-1,3-diamine 352 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2,2,2-trifluoro-ethanone 353 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- [6-(methoxymethyl)pyrimidin-4-yl]-1,2,4-triazol-3-amine 354 2-cyclopropyl-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-morpholino-pyridin-4-amine 355 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-ol 356 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 357 N-[3-morpholino-5-(trifluoromethyl)phenyl]-1-pyrazin-2-yl- 1,2,4-triazol-3-amine 358 N-[3-(3,3a,4,5,7,7a-hexahydro-2H-furo[2,3-c]pyridin-6-yl)-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 359 1-(3,5-difluorophenyl)-N-[3-isopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 360 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-piperazin-2-one 361 1-(3-fluorophenyl)-N-[3-methylsulfonyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 362 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 363 N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 364 1-[6-(methoxymethyl)pyrimidin-4-yl]-N-[3-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 365 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-(4- methylpiperazin-1-yl)pyridin-4-amine 366 N-[3-morpholino-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 367 2-chloro-6-(4-methylpiperazin-1-yl)-N-(1-phenyl-1,2,4-triazol- 3-yl)pyridin-4-amine 368 tert-butyl4-[3-ethyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]piperazine-1-carboxylate 369 N-[3-[(3aR,6aR)-1-methyl-2,3,3a,4,6,6a- hexahydropyrrolo[2,3-c]pyrrol-5-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 370 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]ethanone 371 N-(3-fluoro-5-morpholino-phenyl)-1-(5-fluoro-3-pyridyl)- 1,2,4-triazol-3-amine 372 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-(p-tolyl)-1,2,4- triazol-3-amine 373 1-[3-fluoro-5-[2-methoxyethyl(methyl)amino]phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 374 1-(3,5-difluorophenyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 375 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 376 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 377 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (6-methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 378 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- (1-piperidyl)pyridin-4-amine 379 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrazol-1-ylazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine 380 N-(3-chloro-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine 381 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyrimidin- 5-yl-1,2,4-triazol-3-amine 382 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)pyrrolidin- 3-yl]phenyl]-1,2,4-triazol-3-amine 383 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 384 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 385 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1-(4- pyridyl)-1,2,4-triazol-3-amine 386 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 387 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 388 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluoro-5-methoxy-phenyl)-1,2,4-triazol-3-amine 389 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 390 1-[3-[[ethyl(methyl)amino]methyl]-5-fluoro-phenyl]-N-[3- methyl-5-(4-methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3- amine 391 N-[3-methyl-5-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy- phenyl]-1-phenyl-1,2,4-triazol-3-amine 392 N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-phenyl-1,2,4- triazol-3-amine 393 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2,6- dimorpholino-pyridin-4-amine 394 N-(3-fluoro-5-morpholino-phenyl)-1-(4-fluorophenyl)-1,2,4- triazol-3-amine 395 1-(3-fluoro-5-methoxy-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 396 1-(3,5-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- propyl-phenyl]-1,2,4-triazol-3-amine 397 1-(3-chlorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 398 N-[3-methyl-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]- 1-phenyl-1,2,4-triazol-3-amine 399 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyridazin-4- yl-1,2,4-triazol-3-amine 400 1-(3-chloro-5-fluoro-phenyl)-N-[3-cyclopropyl-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 401 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 402 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]anilino]- 1-piperidyl]ethanone 403 1-(2-fluoro-4-pyridyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 404 N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-(2-pyridyl)-1,2,4- triazol-3-amine 405 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 406 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 407 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- tetrahydropyran-4-yl-pyridin-4-amine 408 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3- piperidyl]phenyl]-1,2,4-triazol-3-amine 409 1-(4-fluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]-1,2,4- triazol-3-amine 410 N-[3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]phenyl]-1- phenyl-1,2,4-triazol-3-amine 411 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3- piperidyl]phenyl]-1,2,4-triazol-3-amine 412 1-(3,4-difluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 413 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,4,5-trifluorophenyl)-1,2,4-triazol-3-amine 414 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(o- tolyl)-1,2,4-triazol-3-amine 415 1-(3-fluoro-5-isopropoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 416 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 417 1-(2,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 418 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 419 N-[3-methyl-5-(2,4,5-trimethylpiperazin-1-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 420 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 421 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 422 methyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate 423 N-[3-methyl-5-[(3R,5S)-3,4,5-trimethylpiperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 424 1-(3-fluoro-5-methyl-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 425 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 426 N-(3-chloro-5-morpholino-phenyl)-1-(3,5-difluorophenyl)- 1,2,4-triazol-3-amine 427 1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 428 1-(2-chlorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 429 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-piperidyl)phenyl]- 1,2,4-triazol-3-amine 430 2-(4-fluoro-1-piperidyl)-6-methyl-N-(1-phenyl-1,2,4-triazol-3- yl)pyridin-4-amine 431 N-[3-methyl-5-[4-[(3-methyloxetan-3-yl)methyl]piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 432 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methoxyphenyl)-1,2,4-triazol-3-amine 433 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 434 N-[3-methyl-5-(4-tetrahydrofuran-3-ylpiperazin-1-yl)phenyl]- 1-phenyl-1,2,4-triazol-3-amine 435 1-(3-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 436 N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 437 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 438 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperidin-3-ol 439 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methylsulfanylphenyl)-1,2,4-triazol-3-amine 440 1-(3,4-difluorophenyl)-N-(3-fluoro-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 441 N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 442 3-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]cyclobutanecarboxylic acid 443 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]pyrrolidin-1-yl]ethanone 444 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-7- azaspiro[3.4]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 445 1-(2,3-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 446 1-(2-chlorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 447 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine 448 N1-cyclopropyl-N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-5-methyl-benzene-1,3-diamine 449 1-[3-[3-methyl-5-[(1-pyrimidin-4-yl-1,2,4-triazol-3- yl)amino]phenyl]-1-piperidyl]ethanone 450 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 451 N-(2-fluoro-3-methyl-5-morpholino-phenyl)-1-(3-pyridyl)- 1,2,4-triazol-3-amine 452 N-(3-fluoro-5-pyrrolidin-3-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine 453 N-[3-[4-(3,3-difluorocyclobutyl)piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 454 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 455 N-[3-[4-(2-fluorophenyl)piperazin-1-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 456 1-(3,5-difluorophenyl)-N-(3-morpholino-5-tetrahydrofuran-3- yl-phenyl)-1,2,4-triazol-3-amine 457 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-(4-fluoro-1- piperidyl)-6-methyl-pyridin-4-amine 458 cyclopropyl-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]methanone 459 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]phenyl]-1,2,4-triazol-3-amine 460 2-cyclopropyl-6-[(3S)-3-fluoropyrrolidin-1-yl]-N-(1-phenyl- 1,2,4-triazol-3-yl)pyridin-4-amine 461 2-methyl-1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]propan-2-ol 462 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluorophenyl)-1,2,4-triazol-3-amine 463 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methylsulfanylphenyl)-1,2,4-triazol-3-amine 464 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 465 N-[3-(2,5-dihydrofuran-3-yl)-5-morpholino-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 466 N-[3-(1-cyclopropyl-3-piperidyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 467 1-[3-fluoro-5-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 468 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 469 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 470 N-[2,3-dimethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 471 N-[2-methoxy-3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 472 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 473 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 475 1-(3,5-difluorophenyl)-N-[3-morpholino-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 476 1-(2-fluoro-5-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 477 2-chloro-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methylpiperazin-1-yl)pyridin-4-amine 478 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine 479 N-[3-methyl-5-[(1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]phenyl]-1-phenyl-1,2,4-triazol- 3-amine 480 [1-[3-fluoro-5-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]phenyl]pyrrolidin-3-yl]methanol 481 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 482 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 483 N-[3-methyl-5-[1-[(3-methyloxetan-3-yl)methyl]-4- piperidyl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 484 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,3,5-trifluorophenyl)-1,2,4-triazol-3-amine 485 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine 486 N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 487 (3R)-3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 488 1-(6-chloro-2-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 489 N-[3-ethyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]- 1-pyrazin-2-yl-1,2,4-triazol-3-amine 490 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(2-methyltetrahydrofuran-2-yl)methyl]benzene-1,3-diamine 491 1-[3-fluoro-5-[(2R)-2-(methoxymethyl)pyrrolidin-1- yl]phenyl]-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 492 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3S)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 493 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]methanol 494 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- [3-fluoro-5-(3-methoxyazetidin-1-yl)phenyl]-1,2,4-triazol-3- amine 495 1-[2-(azepan-1-yl)-4-pyridyl]-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 496 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (2-tetrahydrofuran-2-ylethyl)benzene-1,3-diamine 497 1-(2,4-difluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 498 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 499 3-[3-[3-methyl-5-(4-methylpiperazin-1-yl)anilino]-1,2,4- triazol-1-yl]benzonitrile 500 N-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]pyrrolidin-3-yl]-N-methyl-acetamide 501 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 502 4-methyl-6-(3-morpholinoazetidin-1-yl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-2-amine 503 4-methyl-6-(3-morpholinoazetidin-1-yl)-N-[1-(2-pyridyl)- 1,2,4-triazol-3-yl]pyridin-2-amine 504 N-[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 505 [3-acetoxy-2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]-2-methyl-propyl] acetate 506 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(oxetan-3- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 507 N-[3-[4-(oxetan-3-yl)-1-piperidyl]-5-(trifluoromethyl)phenyl]- 1-pyrazin-2-yl-1,2,4-triazol-3-amine 508 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-6- azaspiro[3.3]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 509 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2-methyl-propanoic acid 510 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrrolidin-1- ylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 511 N-[3-isopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 512 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 513 N-[3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 514 N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 515 1-(3,5-difluorophenyl)-N-[3-[4-fluoro-1-(oxetan-3-yl)-4- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 516 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)piperidin-4-ol 517 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]oxazolidin-2-one 518 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-isopropyl-azetidin-3-ol 519 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]propan-2-ol 520 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(3- methoxycyclobutyl)-5-methyl-benzene-1,3-diamine 521 N-[3-methyl-5-[4-(oxetan-3-yl)-1-piperidyl]phenyl]-1-pyrazin- 2-yl-1,2,4-triazol-3-amine 522 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 523 1-(3-fluorophenyl)-N-[3-isopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 524 4-(difluoromethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 525 4-(difluoromethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 526 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1- phenyl-1,2,4-triazol-3-yl)pyridin-2-amine 527 1-(3,5-difluorophenyl)-N-[3-methyl-5-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)phenyl]-1,2,4-triazol-3-amine 528 N-[3-(3,3a,4,6,7,7a-hexahydro-2H-furo[3,2-c]pyridin-5-yl)-5- methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 529 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- piperazin-1-yl-pyridin-2-amine 530 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(3S)- tetrahydrofuran-3-yl]piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 531 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(3R)- tetrahydrofuran-3-yl]piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 532 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(2- pyridyl)-1,2,4-triazol-3-yl]pyridin-2-amine 533 tert-butyl 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-4-methyl-2-pyridyl]piperazine-1-carboxylate 534 [2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-3-hydroxy-2-methyl-propyl] acetate 535 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine 536 N-[3-isopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 537 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 538 N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 539 N-[3-cyclopropyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 540 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 541 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-8- azaspiro[3.5]nonan-8-yl)phenyl]-1,2,4-triazol-3-amine 542 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]pyrrolidin-2-one 543 1-(3,5-difluorophenyl)-N-[3-methyl-5-(9-oxa-6- azaspiro[3.5]nonan-6-yl)phenyl]-1,2,4-triazol-3-amine 544 N-[3-ethyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-pyrimidin- 5-yl-1,2,4-triazol-3-amine 545 N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 546 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 547 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1-phenyl-1,2,4-triazol-3- yl)-4-(trifluoromethyl)pyridin-2-amine 548 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(2-pyridyl)-1,2,4- triazol-3-yl]-4-(trifluoromethyl)pyridin-2-amine 549 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine 550 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine 551 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-methyl-azetidin-3-ol 552 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (trifluoromethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 553 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-ethyl-azetidin-3-ol 554 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- (trifluoromethyl)-2-pyridyl]-N-ethyl-piperazine-1- carboxamide 555 1-[4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- (trifluoromethyl)-2-pyridyl]piperazin-1-yl]ethanone 556 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-piperazin-1-yl- 4-(trifluoromethyl)pyridin-2-amine 557 tert-butyl 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-4-(trifluoromethyl)-2-pyridyl]piperazine-1- carboxylate 558 1-(2,5-difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)- 1,2,4-triazol-3-amine 559 1-(3,4-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- propyl-phenyl]-1,2,4-triazol-3-amine 560 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- morpholino-pyridin-2-amine 561 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin- 6-one 562 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(4- tetrahydrofuran-3-ylpiperazin-1-yl)pyridin-2-amine 563 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[3- (oxetan-3-yl)azetidin-1-yl]pyridin-2-amine 564 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- tetrahydrofuran-3-ylpiperazin-1-yl)-4-(trifluoromethyl)pyridin- 2-amine 565 ethyl 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 4-methyl-2-pyridyl]piperidine-4-carboxylate 566 N-[3-(3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin- 8-yl)-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 567 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-[4-(oxetan-3- yl)piperazin-1-yl]-6-(trifluoromethyl)pyridin-2-amine 568 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3-fluoro-1- piperidyl)-4-methyl-pyridin-2-amine 569 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]-4-methyl-piperidin-4-ol 570 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(7- oxa-2-azaspiro[3.4]octan-2-yl)pyridin-2-amine 571 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-amine 572 2-[1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]azetidin-3-yl]propan-2-ol 573 N-[3,5-bis(4-tert-butylpiperazin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 574 N-[3,5-bis[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine

In Tables 2A and 2B below, several compounds have stereocenters with either known (R or S) or unknown absolute configurations and/or known (cis or trans) or unknown configurations. For example, compounds 603, 611, 623, 632, 655, 665, 667, 672, 673, 679, 682, 696, 700, 740, 748, 750, 751, 787, 796 and 800 in Table 2A are each single enantiomers with unknown stereochemistry and are arbitrarily assigned the “S” or “R” conformation in the compound name. Compounds 649 and 792 in Table 2B are each single enantiomers of unknown cis/trans configuration and are arbitrarily assigned a trans conformation. Compounds 826 and 861 in Table 2B are each single enantiomers of unknown cis/trans configuration and are arbitrarily assigned a cis conformation.

TABLE 2A Absolute Cmpds No Single Enantiomer Stereochemistry 584 Yes S 603 Yes Unknown 611 Yes Unknown 623 Yes Unknown 628 Yes 1R,4S 632 Yes Unknown 655 Yes Unknown 665 Yes Unknown 667 Yes Unknown 670 Yes 3R 672 Yes Unknown 673 Yes Unknown 679 Yes Unknown 682 Yes Unknown 696 Yes Unknown 700 Yes Unknown 730 Yes S 740 Yes Unknown 748 Yes Unknown 750 Yes Unknown 751 Yes Unknown 787 Yes Unknown 796 Yes Unknown 800 Yes Unknown 822 Yes 1S,4S 831 Yes S

TABLE 2B Cmpds No Single Enantiomer cis/trans 618 Yes cis 649 Yes Unknown 752 Yes trans 792 Yes Unknown 813 Yes trans 826 Yes Unknown 857 Yes trans 861 Yes Unknown

TABLE 2C Compound Names (IUPAC Nomenclature) Cmpd No. IUPAC Name 575 N-[3-methyl-5-(2-morpholinoethoxy)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 576 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1- pyrazin-2-yl-1,2,4-triazol-3-yl)pyridin-2-amine 577 1-(3,4-difluorophenyl)-N-[3-ethyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 578 4-methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 579 4-(1,1-difluoroethyl)-N-[1-(3,4-difluorophenyl)-1,2,4- triazol-3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 580 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- [4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 581 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 582 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-morpholino-methanone 583 N-[3-methyl-5-[[4-(oxetan-3-yl)piperazin-1- yl]methyl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 584 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N-[(1S)-2-methoxy-1-methyl- ethyl]azetidine-3-carboxamide 585 N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 586 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(4-oxa-7- azaspiro[2.5]octan-7-yl)azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 587 1-(3,5-difluorophenyl)-N-[2-fluoro-3-methyl-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 588 5-methyl-N1-(5-methylthiazol-2-yl)-N3-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 589 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]-morpholino-methanone 590 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 591 1-(3,5-difluorophenyl)-N-[3-isopropoxy-2-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 592 3-[4-(oxetan-3-yl)piperazin-1-yl]-5-[(1-phenyl-1,2,4- triazol-3-yl)amino]benzonitrile 593 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2- morpholinoethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 594 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 595 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 596 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[4-(oxetan-3- yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine 597 1-(3-chloro-4-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 598 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 599 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methoxy-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 600 4-methyl-N2-tetrahydrofuran-3-yl-N6-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridine-2,6- diamine 601 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3- morpholinoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2- amine 602 1-(3,5-difluorophenyl)-N-[3-[3-(2,2-dimethylmorpholin-4- yl)azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 603 (5S)-5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4- triazol-3-yl)amino]phenyl]oxazolidin-2-one 604 N1-(1-ethyl-1,2,4-triazol-3-yl)-5-methyl-N3-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 605 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1-methylpyrazol- 3-yl)methoxy]phenyl]-1,2,4-triazol-3-amine 606 1-(4-fluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine 607 2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-4-carbonitrile 608 3-morpholino-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]benzonitrile 609 N-[3-methyl-5-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]phenyl]- 1-(2-pyridyl)-1,2,4-triazol-3-amine 610 4-methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 611 (5S)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-3,5-dimethyl-oxazolidin-2- one 612 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-fluoro-4- (3-morpholinoazetidin-1-yl)pyridin-2-amine 613 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3,5-dimethyl-oxazolidin-2-one 614 N6-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl- N2-tetrahydrofuran-3-yl-pyridine-2,6-diamine 615 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3-methyloxetan-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 616 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-methyl-4- (3-morpholinoazetidin-1-yl)pyridin-2-amine 617 1-(3,5-difluorophenyl)-N-[3-[3-(4-fluoro-1- piperidyl)azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3- amine 618 1-(3,5-difluorophenyl)-N-[3-[3-[(2R,6S)-2,6- dimethylmorpholin-4-yl]azetidin-1-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 619 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 620 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 621 N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin- 2-amine 622 1-(4-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 623 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 624 1-(3-fluoro-4-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 625 4-(methoxymethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N- [1-[3-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2- amine 626 1-[4-[3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenoxy]-1-piperidyl]ethanone 627 1-(3,4-difluorophenyl)-N-[3-methyl-5-(tetrahydropyran-4- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 628 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3-amine 629 1-(3,5-difluorophenyl)-N-[3-methyl-5-[5-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 630 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[[4- (oxetan-3-yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3- amine 631 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-amine 632 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[(3S)-1-(oxetan-3- yl)-3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 633 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 634 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(1- piperidyl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 635 1-(3,5-difluorophenyl)-N-(3-methyl-5-tetrahydropyran-3- yloxy-phenyl)-1,2,4-triazol-3-amine 636 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-6-(3- morpholinoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2- amine 637 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)- 1,4-diazepan-1-yl]phenyl]-1,2,4-triazol-3-amine 638 1-(3,4-difluorophenyl)-N-(3-methyl-5-tetrahydropyran-3- yloxy-phenyl)-1,2,4-triazol-3-amine 639 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4- methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 640 N-[3-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-phenyl]- 1-(3,4-difluorophenyl)-1,2,4-triazol-3-amine 641 1-(3,5-difluorophenyl)-N-[3-isopropoxy-2-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 642 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 643 5-methyl-N3-(1-phenyl-1,2,4-triazol-3-yl)-N1-thiazol-2-yl- benzene-1,3-diamine 644 N-[3-methyl-5-(2-pyrazol-1-ylethoxy)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 645 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-[4-(methoxymethyl)-1-piperidyl]pyridin-2- amine 646 1-(3,5-difluoro-4-methoxy-phenyl)-N-[3-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 647 1-(4-fluoro-3-methyl-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 648 1-(3,5-difluorophenyl)-N-[3-methyl-5-(tetrahydrofuran-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 649 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-(3-morpholinocyclobutyl)benzene-1,3-diamine 650 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methylpiperazin-1-yl)-4-[4-(oxetan-3-yl)piperazin-1- yl]pyridin-2-amine 651 N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 652 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(5-oxa-2- azabicyclo[4.1.0]heptan-2-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 653 1-(3,5-difluorophenyl)-N-[3-isopropoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 654 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- ethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-amine 655 (5R)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-5-methyl-oxazolidin-2-one 656 3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile 657 N-[3,5-bis(4-methylpiperazin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 658 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5-methyl-oxazolidin-2-one 659 1-(3,4-difluorophenyl)-N-[3-methyl-5-[3-(1,4-oxazepan-4- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 660 6-chloro-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4- (3-morpholinoazetidin-1-yl)pyridin-2-amine 661 1-(3,5-difluorophenyl)-N-[3-[3-(1,1-dioxo-1,4-thiazinan-4- yl)azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 662 N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- [3-(trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 663 1-(3,5-difluorophenyl)-N-[3-methyl-5-[6-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 664 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-N- methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-4- carboxamide 665 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[(3R)-1-(oxetan-3- yl)-3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 666 3-morpholino-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]benzonitrile 667 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-2-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 668 3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile 669 N3-(1-isopropylpyrazol-3-yl)-5-methyl-N1-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 670 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(3R)-3- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 671 N-[3-methyl-5-[(3-methyloxetan-3-yl)methoxy]phenyl]-1- [3-(trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 672 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-[(3R)- tetrahydrofuran-3-yl]piperazin-1-yl]-4- (trifluoromethyl)pyridin-2-amine 673 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- [4-[(3R)-tetrahydrofuran-3-yl]piperazin-1-yl]pyridin-2- amine 674 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-4-(trifluoromethyl)pyridin-2-amine 675 methyl 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-6-morpholino-pyridine-4-carboxylate 676 5-methyl-N3-(1-methyl-1,2,4-triazol-3-yl)-N1-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 677 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3-methyloxetan-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 678 3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile 679 (5S)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-5-methyl-oxazolidin-2-one 680 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1- [3-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2- amine 681 5-methyl-N1,N3-bis(1-phenyl-1,2,4-triazol-3-yl)benzene- 1,3-diamine 682 (5R)-5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4- triazol-3-yl)amino]phenyl]oxazolidin-2-one 683 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methyl-3- morpholino-azetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 684 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(3-pyridyl)-1,2,4- triazol-3-yl]-4-(trifluoromethyl)pyridin-2-amine 685 4-(1,1-difluoroethyl)-N-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 686 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-fluoro- N1-(oxetan-3-yl)benzene-1,3-diamine 687 4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]- 1,2,4-triazol-1-yl]benzonitrile 688 N-[3-(2,6-diazaspiro[3.3]heptan-2-yl)-2-fluoro-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 689 N6-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4- methyl-N2-tetrahydrofuran-3-yl-pyridine-2,6-diamine 690 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]-morpholino-methanone 691 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 692 1-(3,5-difluorophenyl)-N-[3-methyl-5-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)phenyl]-1,2,4-triazol-3-amine 693 1-[3-(difluoromethyl)phenyl]-N-[3-methoxy-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 694 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 695 1-(4-fluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 696 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(2R)-2- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 697 1-(3,5-difluorophenyl)-N-[2,5-dimethyl-3-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 698 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2-pyrazol-1- ylethoxy)phenyl]-1,2,4-triazol-3-amine 699 5-methyl-N3-(5-methyl-1H-pyrazol-3-yl)-N1-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 700 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[(3S)-1-(oxetan-3- yl)-3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 701 1-(3,5-difluorophenyl)-N-[3-(3-morpholinoazetidin-1-yl)- 5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 702 6-(4-tert-butylpiperazin-1-yl)-N-[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]-4-methyl-pyridin-2-amine 703 1-(3,5-difluorophenyl)-N-(3-methyl-5-tetrahydrofuran-3- yloxy-phenyl)-1,2,4-triazol-3-amine 704 N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 705 5-chloro-N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]- N1-(oxetan-3-yl)benzene-1,3-diamine 706 N-[3-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-phenyl]- 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 707 6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-2-carbonitrile 708 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 709 N-[3-(4-tert-butylpiperazin-1-yl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 710 1-(4-methoxyphenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 711 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N,N-dimethyl-azetidine-3-carboxamide 712 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1-pyrazin-2-yl-1,2,4- triazol-3-yl)-4-(trifluoromethyl)pyridin-2-amine 713 [2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]-4-pyridyl]methanol 714 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(1-methylpyrazol- 3-yl)methoxy]phenyl]-1,2,4-triazol-3-amine 715 1-(3-chloro-4-methyl-phenyl)-N-[3-ethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 716 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2- amine 717 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 718 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 719 4-(difluoromethyl)-6-(3-morpholinoazetidin-1-yl)-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 720 1-(3,4-difluorophenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 721 1-(3-fluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine 722 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)phenyl]-1,2,4-triazol-3-amine 723 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 724 1-(3,5-difluorophenyl)-N-[3-(2,5-dioxa-8- azaspiro[3.5]nonan-8-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine 725 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-(4- morpholino-1-piperidyl)phenyl]-1,2,4-triazol-3-amine 726 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4,6-bis[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 727 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)phenyl]-1,2,4-triazol-3-amine 728 N-[1-(4-fluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 729 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(methoxymethyl)-1-piperidyl]pyridin-2-amine 730 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(2S)-2- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 731 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (4-methylpiperazin-1-yl)pyridin-2-amine 732 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]-6-(3-morpholinoazetidin-1-yl)pyridin-2-amine 733 6-chloro-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 734 3-[3-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]- 1,2,4-triazol-1-yl]benzonitrile 735 1-(3-fluoro-4-methoxy-phenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 736 1-[3-(difluoromethyl)phenyl]-N-[3-ethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 737 3-[[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile 738 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1,5- dimethyl-N1-(2-morpholinoethyl)benzene-1,3-diamine 739 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 740 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- [4-[(3S)-tetrahydrofuran-3-yl]piperazin-1-yl]pyridin-2- amine 741 5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one 742 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 743 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 744 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (4-piperidyl)pyridin-2-amine 745 N-[3-[4-(3,3-difluoroazetidin-1-yl)-1-piperidyl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 746 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 747 1-(3,5-difluorophenyl)-N-[3-[4-[3- (dimethylamino)propyl]piperazin-1-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 748 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[(3R)-1-(oxetan-3- yl)-3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 749 N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 750 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2R)-2-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 751 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2R)-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 752 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3- morpholinocyclobutoxy)phenyl]-1,2,4-triazol-3-amine 753 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 754 1-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[3-methoxy-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 755 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]piperidin-3-ol 756 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-(3-morpholinoazetidin-1-yl)pyridin-2-amine 757 1-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[3-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 758 N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 759 3-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]- 1,2,4-triazol-1-yl]benzonitrile 760 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-[4-(oxetan- 3-yl)piperazin-1-yl]-6-(trifluoromethyl)pyridin-4-amine 761 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluoro-4-methyl-phenyl)-1,2,4-triazol-3-amine 762 4-[3-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]- 1,2,4-triazol-1-yl]benzonitrile 763 3-morpholino-5-[[1-(3-pyridyl)-1,2,4-triazol-3- yl]amino]benzonitrile 764 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3- methoxy-1-piperidyl)-4-methyl-pyridin-2-amine 765 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-tetrahydrofuran-3-yl-benzene-1,3-diamine 766 N-[3-(3-fluoroazetidin-1-yl)-5-methyl-phenyl]-1-[3-fluoro- 5-(2-methoxyethylamino)phenyl]-1,2,4-triazol-3-amine 767 1-(3-chloro-4-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 768 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4- methyl-6-(3-morpholinoazetidin-1-yl)pyridin-2-amine 769 N-[3-(2-cyclopropylethynyl)-5-methyl-phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 770 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-4-(trifluoromethyl)pyridin-2-amine 771 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3,3,4- trimethylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 772 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(4- methylpiperazin-1-yl)-1-piperidyl]phenyl]-1,2,4-triazol-3- amine 773 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]-pyrrolidin-1-yl-methanone 774 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3,6- dihydro-2H-pyran-4-yl)-4-methyl-pyridin-2-amine 775 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- fluoro-phenyl]oxetan-3-ol 776 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1,4- diazepan-1-yl]phenyl]-1,2,4-triazol-3-amine 777 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]-6-(2-oxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-amine 778 1-(3,4-difluorophenyl)-N-(3-methyl-5-tetrahydrofuran-3- yloxy-phenyl)-1,2,4-triazol-3-amine 779 1-(3-fluoro-4-methyl-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 780 1-(4-fluoro-3-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 781 1-(3-fluoro-4-methoxy-phenyl)-N-[3-fluoro-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 782 1-(3,5-difluoro-4-methoxy-phenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 783 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 784 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3,4- difluorophenyl)-1,2,4-triazol-3-amine 785 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 786 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[3- (methoxymethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 787 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-[(3S)- tetrahydrofuran-3-yl]piperazin-1-yl]-4- (trifluoromethyl)pyridin-2-amine 788 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 789 2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-N- methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-4- carboxamide 790 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 791 2-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]azetidin-3-yl]amino]ethanol 792 N1-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-(3-morpholinocyclobutyl)benzene-1,3-diamine 793 3-[[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile 794 1-[3-(difluoromethyl)phenyl]-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 795 4-(difluoromethyl)-6-[4-(methoxymethyl)-1-piperidyl]-N- [1-[3-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2- amine 796 (5R)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-3,5-dimethyl-oxazolidin-2- one 797 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(3-morpholinocyclobutyl)benzene-1,3-diamine 798 N-[3-(2-cyclopropylethynyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 799 N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(3-morpholinocyclobutyl)benzene-1,3-diamine 800 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(3S)-3- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 801 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- [1-(oxetan-3-yl)-4-piperidyl]pyridin-2-amine 802 N-[3-ethyl-5-[4-(3-methyloxetan-3-yl)piperazin-1- yl]phenyl]-1-(4-fluorophenyl)-1,2,4-triazol-3-amine 803 1-(3,4-difluorophenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 804 N-[3-(difluoromethyl)-5-(3-morpholinoazetidin-1- yl)phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 805 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenoxy]-1-piperidyl]ethanone 806 4-(difluoromethyl)-N-[1-(4-fluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 807 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-(trifluoromethyl)pyridin- 2-amine 808 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(1,4-oxazepan-4- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 809 1-(3,5-difluorophenyl)-N-[3-[4-[2- (dimethylamino)ethyl]piperazin-1-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 810 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-tetrahydropyran-4-yl-benzene-1,3-diamine 811 N-[3-isopropoxy-2-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine 812 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2- morpholinoethoxy)phenyl]-1,2,4-triazol-3-amine 813 N-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenoxy]cyclobutyl]acetamide 814 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-8- azaspiro[4.5]decan-8-yl)phenyl]-1,2,4-triazol-3-amine 815 [1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]-3-piperidyl]methanol 816 1-(3,5-difluorophenyl)-N-[3-[3-(2- methoxyethylamino)azetidin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 817 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N,N-diethyl-azetidine-3-carboxamide 818 N-[3-methyl-5-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]phenyl]- 1-pyrazin-2-yl-1,2,4-triazol-3-amine 819 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 820 1-(3,5-difluorophenyl)-N-[2,5-dimethyl-3-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 821 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]azetidine-3-carbonitrile 822 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3-amine 823 4-(difluoromethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2- amine 824 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N-(2-methoxyethyl)-N-methyl-azetidine-3- carboxamide 825 N-[3-methyl-5-[3-(1,4-oxazepan-4-yl)azetidin-1- yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 826 N1-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-(3-morpholinocyclobutyl)benzene-1,3-diamine 827 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 828 5-methyl-N3-(1-methylpyrazol-3-yl)-N1-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 829 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- fluoro-3-methyl-phenyl)-1,2,4-triazol-3-amine 830 1-(3,5-difluorophenyl)-N-[3-isopropoxy-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 831 N-[3-[(8aS)-7,7-difluoro-1,3,4,6,8,8a- hexahydropyrrolo[1,2-a]pyrazin-2-yl]-5-methyl-phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 832 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-pyrazol-1- ylethoxy)phenyl]-1,2,4-triazol-3-amine 833 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 834 1-(3,4-difluorophenyl)-N-[2-fluoro-5-methyl-3-[[4- (oxetan-3-yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3- amine 835 3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile 836 1-(3-fluoro-4-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 837 4-methyl-6-morpholino-N-[1-[3-(trifluoromethyl)phenyl]- 1,2,4-triazol-3-yl]pyridin-2-amine 838 5-methyl-N1-oxazol-2-yl-N3-(1-phenyl-1,2,4-triazol-3- yl)benzene-1,3-diamine 839 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-(trifluoromethyl)pyridin- 2-amine 840 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[4-(oxetan-3- yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine 841 1-(4-methoxyphenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 842 3-[4-(oxetan-3-yl)piperazin-1-yl]-5-[[1-(3-pyridyl)-1,2,4- triazol-3-yl]amino]benzonitrile 843 6-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-N-[1- (3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-pyridin- 2-amine 845 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2- morpholinoethoxy)phenyl]-1,2,4-triazol-3-amine 846 3,5-dimethyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol- 3-yl)amino]phenyl]oxazolidin-2-one 847 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-fluoro-4- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 848 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4- methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 849 4-(difluoromethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2- amine 850 1-(3,5-difluorophenyl)-N-[3-[4-(3- methoxypropyl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 851 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-oxa-8- azaspiro[4.5]decan-8-yl)phenyl]-1,2,4-triazol-3-amine 852 2-[3-fluoro-5-[3-[3-(3-fluoroazetidin-1-yl)-5-methyl- anilino]-1,2,4-triazol-1-yl]anilino]ethanol 853 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-4-carbonitrile 854 N-[3-methyl-5-(4-morpholino-1-piperidyl)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 855 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(2- methoxyethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 856 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 857 1-(3,5-difluorophenyl)-N-[3-[3-[(2R,6R)-2,6- dimethylmorpholin-4-yl]azetidin-1-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 858 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-(2-morpholinoethyl)benzene-1,3-diamine 859 N-[1-(3-chloro-4-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin- 2-amine 860 4-(1,1-difluoroethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 861 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-(3-morpholinocyclobutyl)benzene-1,3-diamine 862 N-[3-isopropoxy-2-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine 863 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 864 [3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-[4-(oxetan-3-yl)piperazin-1-yl]methanone 865 1-(3,4-difluorophenyl)-N-[3-methyl-5-(tetrahydrofuran-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 866 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (morpholinomethyl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 867 4-(difluoromethyl)-6-morpholino-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 868 N-[3,5-bis(3-morpholinoazetidin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 869 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(3-methyloxetan-3-yl)benzene-1,3-diamine

TABLE 2D Compound Names (IUPAC Nomenclature) Cmpd No. IUPAC Name 870 1-(3,5-difluorophenyl)-N-[2-fluoro-3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 871 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methyl-4- morpholino-pyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 872 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(3- ethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine 873 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- fluoroethyl)-3-piperidyl]-5-methyl-benzene-1,3-diamine 874 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-4-piperidyl]ethanol 875 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]cyclopentanol 876 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3,5-difluorophenyl)-1,2,4- triazol-3-amine 877 3-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-4-piperidyl]propan-1-ol 878 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]cyclohexanol 879 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-4-piperidyl]piperidin-4-ol 880 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-[1-(2-morpholinoethyl)pyrrolidin-3-yl]benzene-1,3- diamine 881 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-[1-(oxetan-3-yl)azetidin-3-yl]benzene-1,3-diamine 882 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[2-(2,6- dimethylmorpholin-4-yl)propyl]-5-methyl-benzene-1,3- diamine 883 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone 884 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(3-pyrrolidin-1-yltetrahydropyran-4-yl)benzene-1,3- diamine 885 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(1,4-dioxan-2-ylmethyl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 886 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)- 1-(3-fluorophenyl)-1,2,4-triazol-3-amine 887 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-N,N-dimethyl-cyclobutanecarboxamide 888 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-tetrahydrofuran- 2-ylmorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 889 N-[3-(1,4-diazabicyclo[3.2.1]octan-4-yl)-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 890 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-tetrahydrofuran- 3-ylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 891 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-[1-(tetrahydrofuran-2-ylmethyl)-4-piperidyl]benzene- 1,3-diamine 892 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(1-methyl-3- piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 893 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[(4- ethylmorpholin-2-yl)methyl]-5-methyl-benzene-1,3- diamine 894 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)pyrrolidin-3-yl]-5-methyl-benzene-1,3- diamine 895 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[(2-morpholinocyclopentyl)methyl]benzene-1,3- diamine 896 1-(3,5-difluorophenyl)-N-[3-[4-(3-methoxypropyl)-1,4- diazepan-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 897 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(1-ethyl- 3-piperidyl)-5-methyl-benzene-1,3-diamine 898 N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine 899 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-(3,3,3-trifluoro-2-morpholino-propyl)benzene-1,3- diamine 900 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]-3-ethoxy-propan-2-ol 901 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-oxa-7- azaspiro[3.4]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 902 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-2-methyl-piperazin-1-yl]ethanol 903 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[(4- isobutylmorpholin-2-yl)methyl]-5-methyl-benzene-1,3- diamine 904 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]butan-1-ol 905 1-cyclopentyl-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]amino]-5-methyl-phenyl]piperazin-2-one 906 1-(3,5-difluorophenyl)-N-[3-(3,7-dioxa-10- azaspiro[5.6]dodecan-10-yl)-5-methyl-phenyl]-1,2,4- triazol-3-amine 907 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)- 1-phenyl-1,2,4-triazol-3-amine 908 N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine 909 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-(oxetan-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 910 1-cyclobutyl-3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]urea 911 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholino-1- piperidyl)phenyl]-1,2,4-triazol-3-amine 912 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(2-morpholinocyclopentyl)benzene-1,3-diamine 913 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)- 1-(3-fluorophenyl)-1,2,4-triazol-3-amine 914 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(tetrahydrofuran- 2-ylmethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 915 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(oxetan-3-yl)benzene-1,3-diamine 916 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriopiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 917 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(2- ethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine 918 N1-(2-cyclopropyltetrahydropyran-4-yl)-N3-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 919 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-2- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine 920 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-methyl-4- morpholino-pyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 921 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]azetidin-3-yl]acetonitrile 922 2-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]ethanol 923 [3-acetoxy-2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]amino]-2-fluoro-5-methyl-phenyl]piperazin-1- yl]propyl]acetate 924 1-(3,5-difluorophenyl)-N-[3-methyl-5-(7-oxa-1- azaspiro[3.5]nonan-1-yl)phenyl]-1,2,4-triazol-3-amine 925 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-methyl-4-(1- methyl-4-piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 926 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-tetrahydropyran-3-yl-piperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 927 1-(3,5-difluorophenyl)-N-[3-[2- (isopropoxymethyl)morpholin-4-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 928 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[2-(2-methylmorpholin-4-yl)ethyl]benzene-1,3- diamine 929 N-[3-[4-(1-deuterio-1-methyl-ethyl)piperazin-1-yl]-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 930 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)-4-piperidyl]-5-methyl-benzene-1,3-diamine 931 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(1-methyl-2-morpholino-ethyl)benzene-1,3-diamine 932 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-(1,4- dioxan-2-ylmethyl)-5-methyl-benzene-1,3-diamine 933 1-(3,5-difluorophenyl)-N-[3-[4-[2- (dimethylamino)ethoxy]-1-piperidyl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 934 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-1-(2-methoxyethyl)pyrrolidin-2-one 935 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(2,2-difluoroethyl)piperazin-1-yl]phenyl]- 1,2,4-triazol-3-amine 936 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(tetrahydrofuran- 3-ylmethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 937 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[[1- (methoxymethyl)cyclopropyl]methyl]-5-methyl-benzene- 1,3-diamine 938 1-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]methyl]-N,N-dimethyl- cyclopentanecarboxamide 939 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(2-morpholinocyclohexyl)benzene-1,3-diamine 940 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[2-(1-oxo-1,4-thiazinan-4-yl)ethyl]benzene-1,3- diamine 941 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-2-methyl-piperazin-1-yl]-2-methyl- propan-2-ol 942 N3-(cyclopropylmethyl)-N1-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 943 N1-(1-cyclobutyl-4-piperidyl)-N3-[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]-2-fluoro-5-methyl-benzene-1,3-diamine 944 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-pyrrolidin-1- ylethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 945 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-pyrrolidin-1- ylpropyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 946 2-[3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-anilino]methyl]azetidin-1-yl]propane- 1,3-diol 947 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-ethyl-piperazin-1-yl)phenyl]-1,2,4-triazol- 3-amine 948 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N,N-dimethyl-piperidin-4-amine 949 1-(3,5-difluorophenyl)-N-[3-[4-(1,4-dioxan-2- ylmethyl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3- amine 950 1-(3,5-difluorophenyl)-N-[3-[4-(2-fluoroethoxy)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 951 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[(1-morpholinocyclopropyl)methyl]benzene-1,3- diamine 952 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)- 1-pyrazin-2-yl-1,2,4-triazol-3-amine 953 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5- methyl-N1-tetrahydrofuran-3-yl-benzene-1,3-diamine 954 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-[(4- methylpiperazin-1-yl)methyl]morpholin-4-yl]phenyl]- 1,2,4-triazol-3-amine 955 N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-fluorophenyl)-1,2,4-triazol-3-amine 956 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(1-methyl-4- piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 957 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]butan-2-ol 958 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]morpholin-2-yl]ethanol 959 2,2,2-trideuterio-1-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1- (3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]ethanone 960 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-[1-(morpholinomethyl)propyl]benzene-1,3-diamine 961 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]methanone 962 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethoxy)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 963 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(3- ethylmorpholin-4-yl)ethyl]-2-fluoro-5-methyl-benzene- 1,3-diamine 964 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]propan-1-ol 965 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 4,5-dimethyl-phenoxy]-1-pyrrolidin-1-yl-ethanone 966 N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5- methyl-phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 967 N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5- methyl-phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 968 N3-[(4-cyclopropylmorpholin-2-yl)methyl]-N1-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 969 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro- N1,5-dimethyl-N1-(oxetan-3-yl)benzene-1,3-diamine 970 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2,2- dimethyltetrahydropyran-4-yl)-5-methyl-benzene-1,3- diamine 971 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 4,5-dimethyl-phenoxy]azetidin-1-yl]ethanone 972 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-tetrahydrofuran- 2-ylmorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 973 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethyl)piperazin- 1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 974 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(5- ethyl-2-methyl-morpholin-4-yl)ethyl]-5-methyl-benzene- 1,3-diamine 975 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(4- methylpiperazin-1-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 976 1-(3,5-difluorophenyl)-N-[3-(4-ethoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 977 1-(3,4-difluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4- triazol-3-amine 978 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 979 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4- triazol-3-amine 980 6-(cyclopropylmethoxy)-N-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-4-methyl-pyridin-2-amine 981 N-[3-(3,4,4a,5,7,7a-hexahydro-2H-furo[3,4-b]pyridin-1- yl)-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol- 3-amine 982 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 983 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine 984 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4- (morpholinomethyl)-1-piperidyl]phenyl]-1,2,4-triazol-3- amine 985 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(2-morpholinobutyl)benzene-1,3-diamine 986 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-3-pyrrolidin- 1-ylpyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine 987 N-[3-[4-[2-(diethylamino)ethyl]piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 988 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3- methylmorpholin-4-yl)-1-piperidyl]phenyl]-1,2,4-triazol-3- amine 989 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 2-fluoro-5-methyl-phenyl]piperazin-1-yl]propane-1,3-diol 990 3-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]propan-1-ol 991 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-tetrahydropyran-4-yl- methanone 992 N1-[1-(2,2-difluoroethyl)-4-piperidyl]-N3-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 993 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-1-pyrrolidin-1-yl-ethanone 994 N-[3-(4-cyclobutyl-2,2,3,3,5,5,6,6-octadeuterio-piperazin- 1-yl)-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4- triazol-3-amine 995 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]propan-2-ol 996 1-(3,5-difluorophenyl)-N-[3-(5-ethyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)-5-methyl-phenyl]-1,2,4- triazol-3-amine 997 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(3-deuteriooxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 998 1-(3,4-difluorophenyl)-N-[2-fluoro-5-methyl-3-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 999 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- tetrahydropyran-3-yloxy-pyridin-2-amine 1001 1-(3,5-difluorophenyl)-N-[3-[4-(4- methoxybutyl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 1002 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)- 1-phenyl-1,2,4-triazol-3-amine 1003 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[2-(2,5- dimethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3- diamine 1004 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]benzene- 1,3-diamine 1005 1-(3,5-difluorophenyl)-N-[3-[4-(2- isopropoxyethyl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 1006 1-(3,5-difluorophenyl)-N-[3-(4-methoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 1007 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(2-morpholinocyclopentyl)benzene-1,3- diamine 1008 N3-[2-(cyclobutoxy)ethyl]-N1-[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]-5-methyl-benzene-1,3-diamine 1009 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1010 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-pyrrolidin-1-yl-pyrrolidin-3-ol 1011 1-(3,5-difluorophenyl)-N-[3-[4-(2-methoxyethyl)-3- methyl-piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3- amine 1012 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1013 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(1-tetrahydropyran-4-yl-4-piperidyl)benzene-1,3- diamine 1014 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydrofuran- 3-yloxy-1-piperidyl)phenyl]-1,2,4-triazol-3-amine 1015 2-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-4-piperidyl]-methyl- amino]ethanol 1016 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5- methyl-N1-(3-methyloxetan-3-yl)benzene-1,3-diamine 1017 N-[3-[2-(diethylaminomethyl)morpholin-4-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1018 1-(3,5-difluorophenyl)-N-[3-[2- [(dimethylamino)methyl]morpholin-4-yl]-5-methyl- phenyl]-1,2,4-triazol-3-amine 1019 1-(3,5-difluorophenyl)-N-[3-(4-isopropoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 1020 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[(3-pyrrolidin-1-yloxetan-3-yl)methyl]benzene-1,3- diamine 1021 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5- methyl-N1-tetrahydropyran-4-yl-benzene-1,3-diamine 1022 N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 1023 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2- methylmorpholin-4-yl)-1-piperidyl]phenyl]-1,2,4-triazol-3- amine 1024 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-3-methyl-piperazin-1-yl]-2-methyl- propan-2-ol 1025 1-(3,5-difluorophenyl)-N-[3-[4-(4-ethylpiperazin-1-yl)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1026 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-1-methyl-piperazin-2-yl]ethanol 1027 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-(pyrrolidin-1- ylmethyl)morpholin-4-yl]phenyl]-1,2,4-triazol-3-amine 1028 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1029 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[(1- methoxycyclobutyl)methyl]-5-methyl-benzene-1,3- diamine 1030 1-(3,5-difluorophenyl)-N-[3-[2-(2- methoxyethyl)morpholin-4-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 1031 1-[3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-anilino]methyl]azetidin-1-yl]ethanone 1032 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3,5-difluorophenyl)-1,2,4- triazol-3-amine 1033 2-[2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]ethoxy]ethanol 1034 N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 1035 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-oxa-7- azaspiro[2.5]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 1036 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]ethanol 1037 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3- methylsulfonylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1038 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-pyrrolidin-1-yl-1- piperidyl)phenyl]-1,2,4-triazol-3-amine 1039 N-[3-[4-(3-deuteriotetrahydrofuran-3-yl)piperazin-1-yl]-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 1040 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]pyrrolidin-3-yl]pyrrolidin-3-ol 1041 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]amino]phenyl]piperazin-1-yl]methanone 1042 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-tetrahydrofuran-3-yl-piperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 1043 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 2-fluoro-5-methyl-phenyl]piperazin-1-yl]ethanol 1044 1-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]ethanone 1045 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-[1-(tetrahydrofuran-3-ylmethyl)-4-piperidyl]benzene- 1,3-diamine 1046 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[(1-tetrahydropyran-4-yl-4-piperidyl)methyl]benzene- 1,3-diamine 1047 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(1-methyl-3- piperidyl)methyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 1048 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2,6- dioxaspiro[4.5]decan-9-yl)-5-methyl-benzene-1,3-diamine 1049 5-methyl-N1-(5-methyloxazol-2-yl)-N3-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 1050 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)-3-piperidyl]-5-methyl-benzene-1,3-diamine 1051 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2- (methylsulfonylmethyl)pyrrolidin-1-yl]phenyl]-1,2,4- triazol-3-amine 1052 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)- 1-phenyl-1,2,4-triazol-3-amine 1053 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1054 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-4-piperidyl]piperidin-3-ol 1055 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1056 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-2-ethyl-piperazin-1-yl]propan-2-ol 1057 1-(3,5-difluorophenyl)-N-[3-methyl-5-(8-oxa-4- azabicyclo[4.2.0]octan-4-yl)phenyl]-1,2,4-triazol-3-amine 1058 N-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]cyclopropanecarboxamide 1059 N1-(1-cyclopropylethyl)-N3-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 1060 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrrolidin-1- ylpyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1061 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)- 1-(3-fluorophenyl)-1,2,4-triazol-3-amine 1062 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[(4-methylmorpholin-3-yl)methyl]benzene-1,3-diamine 1063 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethyl)-3-methyl- piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1064 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N1-(1-tetrahydrofuran-3-yl-4-piperidyl)benzene-1,3- diamine 1065 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2- methoxycyclopentyl)-5-methyl-benzene-1,3-diamine 1066 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 1067 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(2-methoxyethyl)piperazin-2-one 1068 1-(3,5-difluorophenyl)-N-[3-[4-(4-methoxy-1-piperidyl)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1069 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (oxetan-3-ylmethoxy)pyridin-2-amine 1070 N1-(1-cyclobutyl-4-piperidyl)-N3-[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]-5-methyl-benzene-1,3-diamine 1071 1-(3-fluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4- triazol-3-amine 1072 1-(3,5-difluorophenyl)-N-[2-fluoro-3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4- triazol-3-amine 1073 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]morpholin-2-yl]methanol 1074 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-pyrrolidin-1- ylethoxy)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 1075 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-anilino]-3-methyl-azetidin-1-yl]-2-methoxy- ethanone 1076 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-methyl-azetidine-3-carbonitrile 1077 [1-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]pyrrolidin-2- yl]methyl]pyrrolidin-2-yl]methanol 1078 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]-3- (dimethylamino)propan-2-ol 1079 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-fluoro-azetidin-3-yl]methanol 1080 5-deuterio-1-(3,5-difluorophenyl)-N-[3-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1081 1-(3,5-difluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4- triazol-3-amine 1082 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl- N3-[2-(3-methylmorpholin-4-yl)ethyl]benzene-1,3- diamine 1083 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-tetrahydrofuran- 3-ylpyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1084 tert-butyl 3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-anilino]methyl]azetidine-1- carboxylate 1085 N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 1086 N-[3-methyl-5-[4-[1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl]piperazin-1-yl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 1087 N-[3-[2-(cyclopropylmethoxymethyl)morpholin-4-yl]-5- methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 1088 N-[5-deuterio-1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin- 2-amine 1089 N-[5-deuterio-1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- [4-(oxetan-3-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-amine 1090 N-[5-deuterio-1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin- 2-amine 1091 5-deuterio-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-[3-(trifluoromethyl)phenyl]-1,2,4-triazol-3- amine 1092 2-[1-[3-[[5-deuterio-1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]azetidin-3-yl]propan-2-ol 1093 2-cyclopropyl-N-[5-deuterio-1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-6-morpholino-pyridin-4-amine 1094 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 4,5-dimethyl-phenoxy]-1-morpholino-ethanone 1095 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3,4-difluorophenyl)-1,2,4- triazol-3-amine 1096 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[[1-(3,4-difluorophenyl)-1,2,4-triazol- 3-yl]amino]phenyl]piperazin-1-yl]methanone 1097 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 1098 1-(3,4-difluorophenyl)-N-[3-methyl-5-[3-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 1099 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3,4-difluorophenyl)-1,2,4- triazol-3-amine 1100 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,4- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone 1101 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3-fluorophenyl)-1,2,4-triazol- 3-amine 1102 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3-fluorophenyl)-1,2,4-triazol- 3-amine 1103 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3- fluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone 1104 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[[1-(3-fluorophenyl)-1,2,4-triazol-3- yl]amino]phenyl]piperazin-1-yl]methanone 1105 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3- amine 1106 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3- amine 1107 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]methanone 1108 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,3,4,5,6-pentadeuteriophenyl)-1,2,4-triazol-3-amine 1109 N3-benzyl-N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]- 2-fluoro-5-methyl-benzene-1,3-diamine 1110 N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1111 N-[3-methyl-5-(2,2,3,3,5,5,6,6-octadeuterio-4-methyl- piperazin-1-yl)phenyl]-1-phenyl-1,2,4-triazol-3-amine 1112 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]piperazin-1-yl]-tetrahydropyran-4- yl-methanone 1113 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[3-methyl- 4-(1-methyl-4-piperidyl)piperazin-1-yl]phenyl]-1,2,4- triazol-3-amine 1114 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(2- ethylmorpholin-4-yl)ethyl]-2-fluoro-5-methyl-benzene- 1,3-diamine 1115 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-[1-(tetrahydrofuran-3-ylmethyl)-4- piperidyl]benzene-1,3-diamine 1116 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-[1-(tetrahydrofuran-2-ylmethyl)-4- piperidyl]benzene-1,3-diamine 1117 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[3-(4- methylpiperazin-1-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1118 N3-[(4-cyclopropylmorpholin-2-yl)methyl]-N1-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- benzene-1,3-diamine 1119 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(1-methyl-2-morpholino-ethyl)benzene-1,3- diamine 1120 1-(3,5-difluorophenyl)-N-[2-fluoro-3-[2- (isopropoxymethyl)morpholin-4-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 1121 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N3-[(1-morpholinocyclopropyl)methyl]benzene- 1,3-diamine 1122 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(3- tetrahydrofuran-3-ylazetidin-1-yl)phenyl]-1,2,4-triazol-3- amine 1123 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 2-fluoro-5-methyl-phenyl]-2-methyl-piperazin-1-yl]-2- methyl-propan-2-ol

Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically Acceptable Salts and Compositions

As discussed herein, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for the treatment of neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy. In one embodiment, said neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy include, but are not limited to spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophyiLeber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, essential tremor or osmotic hyponatremia.

In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor-sphincter dyssynergia, erectile dysfunction or anorgasmy.

Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also useful for treating or lessening the severity of, in a subject, a disease or disorder selected from neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of the compounds of formula I or I′ and one or more pharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In one embodiment, the methods described herein also provide a method of promoting oligodendrocyte proliferation, differentiation or survival comprising contacting oligodendrocytes with a compound of formula I or I′ or a composition thereof.

In another embodiment, a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival. In another embodiment, a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival with a compound of formula I or I′ or a composition thereof. In another embodiment, a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or disorder associated with a lack of oligodendrocyte proliferation, differentiation or survival comprising administering a therapeutically effective amount of the compounds of formula I or I′ or compositions thereof to a subject in need thereof.

In another embodiment, a method of the present invention comprises promoting myelination by contacting neuronal cells, oligodendrocyte cells or oligodendrocyte precursor cells. In one embodiment, a method of the present invention comprises promoting myelination by contacting neuronal cells, oligodendrocyte cells or oligodendrocyte precursor cells with a compound of formula I or I′ or a composition thereof.

In another embodiment, a method of the present invention comprises promoting survival of cells of the nervous system. In another embodiment, a method of the present invention comprises promoting survival of cells of the nervous system comprising contacting the cells with a compound or composition of formula I or I′. In one embodiment, the cells of the nervous system comprise brain cells, cortical neurons, oligodendroctyes or oligodendrocyte precursor cells.

In another embodiment, a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or condition associated with demyelination comprising administering a therapeutically effective amount of the compounds of formula I or I′ or compositions thereof to a subject in need thereof. In one embodiment, the disease or condition associated with demyelination is a CNS disorder or a CNS demyelinating disease as described herein. In one embodiment, the disease is multiple sclerosis.

In another embodiment, the subject has, or is at risk of having, multiple sclerosis. The subject with multiple sclerosis can be at any stage of treatment or disease. In one embodiment, the subject with multiple sclerosis has one or more of: benign multiple sclerosis, relapsing remitting multiple sclerosis, quiescent relapsing remitting multiple sclerosis, active relapsing remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis, clinically isolated syndrome, or clinically defined multiple sclerosis. In one embodiment, the type of multiple sclerosis is primary progressive multiple sclerosis. In another embodiment, the type of multiple sclerosis is relapsing-remitting multiple sclerosis. In yet another embodiment, the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further embodiment, the type of multiple sclerosis is progressive relapsing multiple sclerosis. In another embodiment, the subject is asymptomatic. In another embodiment, the subject has one or more multiple sclerosis-like symptoms, such as those having clinically isolated syndrome or clinically defined multiple sclerosis. In yet other embodiments, the subject has one or more multiple sclerosis relapses.

In another embodiment, the subject has a relapsing form of multiple sclerosis such as relapsing remitting multiple sclerosis or relapsing secondary progressive multiple sclerosis. In one embodiment, the subject has relapsing remitting multiple sclerosis and has one or more ongoing clinical exacerbations. In another embodiment, the subject has relapsing remitting multiple sclerosis and one or more subclinical activities. In one embodiment, the clinical exacerbation or subclinical activity is shown by gadolinium enhancement of white matter lesions using T1/T2 magnetic resonance imaging. In another embodiment, the clinical exacerbation or subclinical activity is shown by development of new or enlarged white matter lesions on magnetic resonance imaging of the brain or spinal cord. In one embodiment, the development of new or enlarged white matter lesions is monitored by T1/T2 magnetic resonance imaging. In another embodiment, the development of new or enlarged white matter lesions is monitored by Proton Density magnetic resonance imaging. In yet another embodiment, the development of new or enlarged white matter lesions is monitored by MTR magnetic resonance imaging. See also, Gaitán, M. I. and Reich, D. S. (2014) MRI in Diagnosis and Disease Monitoring, in Multiple Sclerosis and CNS Inflammatory Disorders (eds L. M. Samkoff and A. D. Goodman), John Wiley & Sons, Ltd., Chichester, UK. doi: 10.1002/9781118298633.ch4 which is incorporated herein in its entirety by reference.

In another embodiment, the clinical exacerbations or subclinical activities are monitored by a functional readout such as ambulatory changes (gait changes, sway changes, etc.), T25W changes and/or EDSS changes. In another embodiment, the clinical exacerbations or subclinical activities are monitored by a visual evoked potential assay, a visual acuity assay or a measurement of optic nerve thickness. In another embodiment, the clinical exacerbations or subclinical activities are monitored by a myelin labelling assay.

In another embodiment, the subject with multiple sclerosis can be at any stage of treatment or disease and treatment with compounds of formula I or I′ of the present invention result in improvement of the disease or symptoms. In one embodiment, improvement in the disease or symptoms is evidenced by a reduction or disappearance of one or more white matter lesions in the brain. In another embodiment, improvement in the disease or symptoms is evidenced by improved function such as improved ambulation, improved gait, reduced sway, improved T25W scores or improved EDSS scores. In another embodiment, improvement in the disease or symptoms is evidenced by improvements in a visual acuity assay or a visual evoked potential assay. In another embodiment, improvement in the disease or symptoms is evidenced by enhanced optic nerve thickness. In another embodiment, improvement in the disease or symptoms is evidenced by increased myelination in a myelin labelling assay.

In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive demyelinating diseases. In one embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in primary progressive multiple sclerosis. In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in secondary progressive multiple sclerosis. In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in relapsing-remitting multiple sclerosis. In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive relapsing multiple sclerosis.

In yet another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein oligodendrocyte cells are stimulated to regenerate or differentiate. In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein oligodendrocyte cells are stimulated to remyelinate axons.

In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level whereby oligodendrocyte cells are stimulated to regenerate or differentiate thereby treating demyelinating diseases or disorders. In yet another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level whereby axons are remyelinated by oligodendrocyte cells thereby treating demyelinating diseases or disorders.

In another embodiment, the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein are useful for inducing endogenous oligodendrocytes or oligodendrocyte precursor cells to contact an axon and produce myelin.

In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or I′.

In one aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophyiLeber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, essential tremor or osmotic hyponatremia comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or I′.

In another aspect, the present invention provides a method of treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor-sphincter dyssynergia, erectile dysfunction or anorgasmy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or I′.

In yet another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or I′ with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, essential tremor or osmotic hyponatremia comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or I′ with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis. In one aspect, the type of multiple sclerosis is primary progressive multiple sclerosis. In another aspect, the type of multiple sclerosis is relapsing-remitting multiple sclerosis. In yet another aspect, the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further aspect, the type of multiple sclerosis is progressive relapsing multiple sclerosis.

In another aspect, the present invention provides a method for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor-sphincter dyssynergia, erectile dysfunction or anorgasmy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or I′ with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

Manufacture of Medicaments

In one aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoencephalopathy.

In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, essential tremor or osmotic hyponatremia.

In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor-sphincter dyssynergia, erectile dysfunction or anorgasmy.

In yet another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

In one aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoencephalopathy with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, essential tremor or osmotic hyponatremia in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis. In one aspect, the type of multiple sclerosis is primary progressive multiple sclerosis. In another aspect, the type of multiple sclerosis is relapsing-remitting multiple sclerosis. In yet another aspect, the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further aspect, the type of multiple sclerosis is progressive relapsing multiple sclerosis.

In yet another aspect, the present the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor-sphincter dyssynergia, erectile dysfunction or anorgasmyin combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

Administration of Pharmaceutically Acceptable Salts and Compositions

In certain embodiments of the invention an “effective amount” of the compound, a pharmaceutically acceptable salt thereof or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of, in a subject, a disease or disorder selected from one or more of a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoencephalopathy.

The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Additional Therapeutic Agents

It will also be appreciated that the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

In one embodiment, the additional therapeutic agents is an immunomodulatory agent, such as an IFN-β 1 molecule including but not limited to an interferon beta 1a (Avonex®, Rebif®) or an interferon beta 1b (Betaseron®, Betaferon®, Extavia®). Immunomodulatory agents also include other interferons and fragments, analogues, homologues, derivatives, and natural variants thereof with substantially similar biological activity to interferon beta 1a molecules.

In another embodiment, the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).

In another embodiment, the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).

In another embodiment, the additional therapeutic agent is an anthracenedione molecule such as mitoxantrone (Novantrone®).

In another embodiment, the additional therapeutic agent is a sphingosine 1-phosphate receptor modulator such as fingolimod (Gilenya®) and those described in WO 2012/109108 the entire contents of which is hereby incorporated by reference.

In another embodiment, the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).

In another embodiment, the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).

In another embodiment, the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).

In another embodiment, the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).

In another embodiment, the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.

In another embodiment, the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.

In another embodiment, the additional therapeutic agent is an anti-VLA4 antibody, such as Natalizumab (Tysabri®) or a related VLA-4 antibodies such as those described in U.S. Pat. No. 5,840,299, U.S. Pat. No. 6,602,503, Sanchez-Madrid et al, (1986) Eur. J. Immunol 16: 1343-1349; Hemler et al, (1987) J Biol. Chem. 2: 11478-11485; Issekutz et al. (1991) J Immunol 147: 109 (TA-2 mab); Pulido et al. (1991) J Biol. Chem. 266: 10241-10245; and U.S. Pat. No. 5,888,507 the entire contents of each patent or publication hereby incorporated by reference in their entirety.

In another embodiment, the additional therapeutic agent is a LINGO-1 antagonist (e.g., an antibody against LINGO (e.g., LINGO-1, LINGO-2, LINGO-3, LINGO-4) or a Nogo receptor-1 (NgR1) modulator and compositions thereof such as those disclosed in WO2004/085648, WO2006/002437, WO2007/008547, WO2007/025219, WO2007/064882, WO2007/056161, WO2007/133746, WO2007/098283, WO2008/086006, WO2009/061500, WO2010/005570, WO2010/062904, WO 2013/173364, WO2014/058875, each of which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a TAJ modulator, such as those disclosed in WO2006/017673, which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a TrkA antagonist such as those disclosed in WO2008/013782 or a TrkB antagonist such as those disclosed in WO2009/048605, each of which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a sclerostin modulator such as those disclosed in WO2013/063095, which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is an autotaxin (ATX) inhibitor or LPA receptor antagonist, such as those described in WO2015048301, WO2015042053, WO2015042052, WO2015008230, WO2015008229, WO2014202458, WO2014139882, WO2014133112, WO2014097151, WO2014110000, WO2014/081756, WO2014/081752, WO2014/048865, WO2014168824, WO2014143583, WO2014139978, WO2013/186159, WO2012/024620, WO2012/166415, WO2012078593, WO2012078805, WO2012024620, WO2013070879, WO2013/061297, WO2013/054185, WO2014/018881, WO2014/018887, WO2014/018891, WO2014/025708, WO2104/025709, WO2014/152725, WO2012028243, WO2012005227, WO2011/159635, WO2011/159550, WO2011116867, WO2011053948, WO2011041729, WO2011041694, WO2011041462, WO2011041461, WO2011017561, WO2011017350, WO2010115491, WO2011006569, WO20110141761, WO2010112124, WO2010112116, WO2010077883, WO2010077882, WO2010068775, WO2010063352, WO2010051031, WO2010051030, WO2009046841, WO2009046842, WO2009046804, WO2009023854, WO2009/135590, WO2008/014286, WO 2010/141768, US2006/194850, US 2003/114505, US 2004/122236, US 2006/194850, U.S. Pat. No. 6,964,945, US2005/0256160, US 2006/148830, US 2008/0293764, US2010/0249157, the disclosure of each patent application and patent hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a Nox4 modulator such as those described in WO2013/037499, which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a remyelinating antibody such as rHIgM22.

In another embodiment, the additional therapeutic agent is dalfampridine (Ampyra®)

In another embodiment, the additional therapeutic agent is a death receptor 6 (DR6) antagonist, a p75 antagonist or a combination thereof such as those disclosed in U.S. Pat. No. 8,894,999 and WO2014106104 each of which is incorporated herein by reference in its entirety.

In another embodiment, the additional therapeutic agent is Cethrin™.

In another embodiment, the additional therapeutic agent is an activin receptor modulator such as those described in WO2015/001352, which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a GLP-1 like peptide or a derivative of GLP-1 like peptides such as those disclosed in WO2015/000942, WO2014/202727, WO2012/140117, WO2012/062803, WO 2012/062804, WO2011/080102 and WO2009/030771, each of which is incorporated herein by reference in its entirety. In another embodiment, the GLP-1 derivative is Liraglutide or Semaglutide.

In another embodiment, the additional therapeutic agent is a RXR modulator such as those disclosed in US2015/0038585 and WO2013056232 each of which is incorporated herein by reference in its entirety. In another embodiment, the RXR modulator is HX630.

In another embodiment, the additional therapeutic agent is an activator of the NRF2/KEAP1/ARE pathway such as those disclosed in WO2014/197818 which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a PPAR agonist such as those disclosed in WO2014/165827 which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is an inhibitor of HDAC4 such as those disclosed in WO2013/080120 which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a gamma secretase inhibitor such as DAPT.

In another embodiment, the additional therapeutic agent is an antipsychotic medication such as quetiapine.

In another embodiment, the additional therapeutic agent is a thyroid hormone.

In another embodiment, the additional therapeutic agent is a thyroid translocator protein (TSPO) such as etifoxine.

In another embodiment, the additional therapeutic agent is insulin-like growth factor 1 (IGF-1).

In another embodiment, the additional therapeutic agent is an anticholinergic such as benzatropine.

In another embodiment, the additional therapeutic agent is an antihistamine/anticholinergic such as clemastine or clemastine fumarate.

In another embodiment, the additional therapeutic agent is one that removes antiaquaporin by plasmapheresis.

In another embodiment, the additional therapeutic agent is a hyaluronan inhibitor or antagonist such as those described in WO2015023691, which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a hyaluronidase inhibitor such as a PH20 inhibitor or those described in WO2013/102144, WO2011/133862, and WO2010/007729 each of which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a Toll-Like Receptor-2 (TLR-2) inhibitor.

In another embodiment, the additional therapeutic agent is a Semaphorin 3A antagonist or antibody such as those disclosed in WO2014123186, which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a CXCR2 inhibitor or antagonist.

In another embodiment, the additional therapeutic agent is a Semaphorin 3F agonist.

In another embodiment, the additional therapeutic agent is a Wnt polypeptide or Wnt inhibitor such as those disclosed in WO 2013/040309 and WO 2012/097093, each of which is hereby incorporated by reference in its entirety.

In another embodiment, the additional therapeutic agent is a mitochondrial pore modulator such as Olesoxime.

In another embodiment, the additional therapeutic agent is a PSA NCAM antagonist, a CXCR2 inhibitor or antagonist, a MRF agonist, a GM-98 agonist, a Tcf4 inhibitor, a retinoid, a neuregulin 1-erbB signaling modulator, a zpf191 activator, an miR219 activator, an miR338 activator or an miR138 activator.

In certain embodiments, the additional agent is an immunomodulatory agent such as an IFN-β 1 molecule which is administered intravenously, subcutaneously or intramuscularly. In one embodiment, the IFN-β 1 molecule is administered at 20-45 microgram once a week by intramuscular injection. In another embodiment, the IFN-β 1 molecule is administered at 20-30 microgram three times a week by intramuscular injection. In another embodiment, the IFN-β 1 molecule is administered at 40-50 micrograms once a week, by subcutaneous injection.

In another embodiment, the IFN-β 1 molecule is administered in an amount of between 10 and 50 μg intramuscularly three times a week.

In another embodiment, the IFN-β 1 molecule is administered in an amount of between 10 and 50 μg intramuscularly every five to ten days.

In another embodiment, the IFN-β 1 molecule is administered in an amount between 200 and 600 μg every other day by subcutaneous injection. In one embodiment, the IFN-β 1 molecule is an interferon β-1b (Betaseron®, Betaferon®, or Extavia®).

These combinations are useful for treating or lessening the severity of, in a subject, the diseases described herein including neurodegenerative diseases such as multiple sclerosis. These combinations are also useful in the kits described herein.

It will also be appreciated that the compounds of formula I or I′ of the present invention and the methods, compositions and kits disclosed herein can be employed in combination therapies to not only treat or lessen the severity of, in a subject, the diseases described herein but may also be used in symptom management. Those additional agents include those useful for treating symptoms such as bladder problems (e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®); infections (Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®); bowel dysfunction (Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesi®a, glycerin suppositories); depression (Cymbalta®, Effexor®, Paxil®, Prozac®, Wellbutrin®, Zoloft®); dizziness and vertigo (Antivert®); emotional changes (Nuedexta®), Fatigue (Amantadine®, Provigil®, Prozac®), itching (Atarax®); pain (Dilantin®, Elavil®, Klonipin®, Neurontin®, Pamelor®, Aventyl®, Tegetrol®); sexual problems (Cialis®, Levitra®, Papaverine®, MUSE®, Prostin VR®, Viagra®); spasticity (Dantrium®, Gablofen®, Klonipin®, Lioresal®, Valium®, Zanaflex®); tremors (Laniazid®, Nydrazid®, Klonopin®, Rivotril®); and walking or gait difficulties (Ampyra®).

The amount of additional therapeutic agent present in or with the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

In another aspect, the present invention features a kit comprising a compound and/or pharmaceutical composition of formula I or I′ of the present invention and instructions for use thereof.

In another embodiment, the kits of the present invention further comprise one or more additional therapeutic agent(s). In another embodiment, the additional therapeutic agent is selected from an immunomodulatory agent, such as an IFN-β 1 molecule including but not limited to an interferon beta 1a (Avonex®, Rebif®) or an interferon beta 1b (Betaseron®, Betaferon®, Extavia®).

In another embodiment, the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).

In another embodiment, the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).

In another embodiment, the additional therapeutic agent is an anthracenedione molecule such as mitoxantrone (Novantrone®).

In another embodiment, the additional therapeutic agent is a sphingosine 1-phosphate receptor modulator such as fingolimod (Gilenya®) and those described in WO 2012/109108 the entire contents of which is hereby incorporated by reference.

In another embodiment, the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).

In another embodiment, the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).

In another embodiment, the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).

In another embodiment, the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).

In another embodiment, the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.

In another embodiment, the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.

In another embodiment, the additional therapeutic agent is one or more compounds useful for treating symptoms of the disease such as bladder problems (e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®); infections (Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®); bowel dysfunction (Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesia®, glycerin suppositories); depression (Cymbalta®, Effexor®, Paxil®, Prozac®, Wellbutrin®, Zoloft®); dizziness and vertigo (Antivert®); emotional changes (Nuedexta®), Fatigue (Amantadine®, Provigil®, Prozac®), itching (Atarax®); pain (Dilantin®, Elavil®, Klonipin®, Neurontin®, Pamelor®, Aventyl®, Tegetrol®); sexual problems (Cialis®, Levitra®, Papaverine®, MUSE®, Prostin VR®, Viagra®); spasticity (Dantrium®, Gablofen®, Klonipin®, Lioresal®, Valium®, Zanaflex®); tremors (Laniazid®, Nydrazid®, Klonopin®, Rivotril®); or walking or gait difficulties (Ampyra®).

In another embodiment, the kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in separate containers.

In another embodiment, the kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in the same container.

In another embodiment, the container is a bottle, vial, or blister pack, or combination thereof.

SCHEMES AND EXAMPLES

The compounds of the invention may be readily prepared by known methods and by using the following methods, schemes and examples. Illustrated below in Scheme A through Scheme Q are general methods for preparing the compounds of the present invention. Compounds were named using either IUPAC nomenclature or the nomenclature used in ChemBioDraw Ultra (Version 12.0.2.1076, CambridgeSoft®). Anywhere in the present application where a name of a compound may not correctly describe the structure of the compound, the structure supersedes the name and governs.

EXAMPLES General Methods

¹H NMR (obtained on a Bruker 400 MHz Advance III QNP probe 1H/13C/19F/31P or a Bruker 300 MHz Advance I QNP probe 1H/13C/19F/31P) spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d₆ (DMSO-D6 or DMSO-d6). Mass spectra (MS) were obtained using either Method 1 or Method 2 as follows. Method 1: Mass spectra (MS) were obtained using a Waters Acquity UPLC-MS system equipped with a Waters 3100 mass detector. Compound purity and retention times were determined by reversed phase HPLC using an Acquity CSH C18 column (50×2.1 mm, 1.7 μm particle) from Waters (pn: 186005296), and a dual gradient run from 5-95% mobile phase B over 0.60 minutes. Mobile phase A=H₂O (0.1% CF₃CO₂H). Mobile phase B=CH₃CN (0.1% CF₃CO₂H). Flow rate=0.6 mL/min, injection volume=2 μL, and column temperature=25° C. Method 2: Mass spectra (MS) were obtained using a Waters Acquity UPLC-MS system equipped with a Waters 3100 mass detector. Compound purity and retention times were determined by reversed phase HPLC using an Acquity CSH Fluoro Phenyl column (50×2.1 mm, 1.7 μm particle) from Waters (pn: 186005351), and a dual gradient run from 5-95% mobile phase B over 0.60 minutes. Mobile phase A=H₂O (0.1% CF₃CO₂H). Mobile phase B=CH₃CN (0.1% CF₃CO₂H). Flow rate=0.6 mL/min, injection volume=2 μL, and column temperature=25° C. Normal phase flash chromatography was performed using pre-packed Isco RediSepRf high performance columns. Pyridine, dichloromethane (CH₂Cl₂ or DCM), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and 1,4-dioxane were from Baker or Aldrich and in some cases the reagents were Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were stirred magnetically unless otherwise noted.

The following definitions describe terms and abbreviations used herein:

-   DCM dichloromethane -   DMA diemethylacetamide -   EtOAc/EA ethyl acetate -   Hex hexanes -   HEP heptanes -   HPLC high-performance liquid chromatography -   LCMS liquid chromatography-mass spectrometry -   ESI-MS electrospray ionization mass spectrometry -   TLC thin layer chromatography -   DMF N,N-dimethylformamide -   DMSO dimethylsulfoxide -   THF tetrahydrofuran -   Et₃N triethylamine -   NMP N-methylpyrrolidone -   HOAc acetic acid -   TFA trifluoroacetic acid -   ACN acetonitrile -   DCM dichloromethane -   DCE dichloroethane -   DMA dimethylacetamide -   N2 nitrogen -   R.T./RT/rt room temperature -   AT ambient temperature -   MeOH methanol -   EtOH ethanol -   t-BuOH t-butanol -   t-BuONa sodium t-butoxide -   Pd/C palladium on carbon -   SnAr nucleophilic aromatic substitution mechanism -   t-BuXPhos Palladacycle     chloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)     [2-(2-aminoethyl)phenyl]palladium(II) -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium -   ISCO flash chromatography system -   SiO₂ silica gel -   MP-TMT macroporous polystyrene-bound trimecaptotriazine -   PL-HCO₃ MP SPE polymer supported bicarbonate resin -   RBF round-bottom flask -   Cmpd Compound

Compounds of the invention may be prepared as generally outlined in Scheme A, which shows representative structures wherein L¹ is a bond, the piperazinyl may represent G¹ or G², R¹⁰⁰ may represent -L²-R⁶, -L²-R⁷, or optional G² substituents, R⁴⁰ may represent optional R⁴ substituents, and R², R³, X¹, and X² are as defined herein. The methods of Scheme A may also be applied to other variations of L¹ with G¹ to G⁵ that bond to the parent molecular moiety through a nitrogen atom.

Example 1 Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 33)

(a) t-BuXPhos Palladacycle, t-BuOH, t-BuONa, 60° C.; (b) Pd on Carbon, 10% WT Degussa, H₂; (c) Cu(OAc)₂/Pyridine/CH₂Cl₂/room temp; (d) t-BuXPhos Palladacycle, t-BuOH

Preparation of 1-(3-methyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine (JW-1a)

Sodium 2-methylpropan-2-olate (10.5 g, 109.4 mmol), 1-(oxetan-3-yl)piperazine (6.28 g, 44.2 mmol), t-BuXPhos Palladacycle (93 mg, 0.88 mmol) and 1-bromo-3-methyl-5-nitro-benzene (9.54 g, 44.1 mmol) were mixed in 2-methylpropan-2-ol (50 mL) and the reaction was degassed with N₂ for 10 seconds. The reaction was stirred at 60 degrees for 3 hours and LCMS indicated that the reaction was complete. The reaction was quenched with 1 ml water and the mixture was extracted with DCM (3×3 ml). The combined DCM layers were dried over Na₂SO₄, concentrated and purified on silica gel (120 grams column, 10-90% ethyl acetate:hexanes) to afford 5.9 g (31%) of desired product JW-1a. ¹H NMR (300 MHz, CDCl3) δ 7.61-7.42 (m, 2H), 7.00 (s, 1H), 4.68 (dt, J=12.4, 6.4 Hz, 4H), 3.67-3.46 (m, 1H), 3.41-3.17 (m, 4H), 2.59-2.44 (m, 4H), 2.40 (s, 3H) ppm. ESI-MS m/z calc. 277.14264. found 278.45; (M+1)+; Retention time: 0.57 minutes.

Preparation of 3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline (JW-1b)

To a 250 ml RBF was added Pd on carbon 10% WT, Degussa (250 mg, 2.3 mmol) under N2 and EtOH (60 mL) was added into the reaction under N2. 1-(3-Methyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine JW-1a (6.5 g, 23.4 mmol) was added and the reaction was stirred at R.T. under a hydrogen balloon. The reaction was stirred overnight and LCMS showed that the reaction was complete. The catalyst was filtered off and the filtrated was concentrated to afford 5.34 g (92%) of desired product JW-1b. ¹H NMR (300 MHz, CDCl3) δ 6.19 (s, 1H), 6.08 (d, J=1.5 Hz, 2H), 4.80-4.48 (m, 4H), 3.73-3.39 (m, 3H), 3.31-3.08 (m, 4H), 2.66-2.38 (m, 4H), 2.22 (s, 3H) ppm. ESI-MS m/z calc. 247.16846. found 248.48; (M+1)+; Retention time: 0.25 minutes.

Preparation of 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole (JW-1c)

3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole was prepared by either Method 1 or Method 2 as follows.

Method 1: Diacetoxycopper (2.30 g, 12.7 mmol), 3,5-difluorophenyl-boronic acid (1.60 g, 10.1 mmol), 3-bromo-1H-1,2,4-triazole (1.25 g, 8.4 mmol) and 4A molecular sieve (150 mg) were mixed in DCM (50 mL), and pyridine (1.3 mL, 16.90 mmol) was added. The mixture was stirred at RT under air for 3 days. LCMS showed that no starting material remained and desired product was formed. The reaction was filtered through a plug of Celite via suction and the solid was washed with additional DCM (200 ml). The combined organic layer was washed with 0.1 N aqueous HCl three times (50 ml×3) and brine (200 ml). The organic layer was concentrated and purified on silica gel (120 g column, dry loading method on Celite) using 10-90% EtOAc:Hexanes to afford 1.23 g (50%) of desired product JW-1c. ¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.78-7.61 (m, 2H), 7.41 (tt, J=9.3, 2.3 Hz, 1H) ppm. ESI-MS m/z calc. 258.95566. found 260.05; (M+1)+; Retention time: 0.8 minutes.

Method 2: A DMSO (100 mL) mixture of 3-bromo-1H-1,2,4-triazole (2.95 g, 20 mmol), 1,3,5-trifluorobenzene (10.57 g, 80.0 mmol) and K₂CO₃ (6.63 g, 48.0 mmol) was stirred at 109° C. overnight. Both TLC and LCMS indicated the major peak to be the desired product. To the reaction mixture was added brine and EtOAc, the organic phase was dried over MgSO₄, filtered, concentrated in vacuo and purified on an ISCO system using 80 g silica gel column eluting with 75% heptanes and 25% EtOAc to give (1.3 g, 25%) of the desired product, 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole (1.3 g, 4.99 mmol, 25%). ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 7.28 (td, J=4.1, 2.2 Hz, 2H), 6.90 (tt, J=8.6, 2.3 Hz, 1H) ppm. ESI-MS m/z calc. 258.95566. found 262.01; (M+1)⁺; Retention time: 0.79 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 33)

Sodium t-butoxide (669 mg, 6.96 mmol), 3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline JW-1b (852 mg, 3.44 mmol), 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole JW-1c (902 mg, 3.46 mmol) and t-BuXPhos Palladacycle (83 mg, 0.12 mmol) were mixed in t-BuOH (12 mL) and the reaction was degassed with N₂ for 30 seconds. The reaction was stirred and heated at 60 degrees for 3 hours and the LCMS indicated that the reaction was complete. The reaction was quenched with 1 ml water and brine was added into the solution. The reaction was extracted with DCM (3×30 ml) and the combined organic layer was washed with water and brine. The organic layer was dried over Na₂SO₄, concentrated in vacuo and the crude was purified on silica gel (12 gram column, 10-100% EtOAc:Hexanes) to afford 768 mg (51%) of desired cmpd 33. ¹H NMR (300 MHz, CDCl₃) δ 8.32 (s, 1H), 7.28-7.21 (m, 2H), 7.12 (t, J=1.9 Hz, 1H), 6.88-6.68 (m, 3H), 6.46 (d, J=14.4 Hz, 1H), 4.81-4.70 (m, 4H), 3.67-3.48 (m, 1H), 3.33 (dd, J=13.0, 8.2 Hz, 4H), 2.61-2.51 (m, 4H), 2.35 (s, 3H) ppm. ESI-MS m/z calc. 426.19797. found 427.36; (M+1)+; Retention time: 0.65 minutes.

Example 2 Preparation of 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 406)

Preparation of 3-bromo-1-(3-fluorophenyl)-1,2,4-triazole (JW-2c)

3-bromo-1H-1,2,4-triazole (9.6 g, 64.9 mmol), pyridine (10.5 mL, 129.8 mmol), copper (II) acetate (17.7 g, 97.3 mmol) and (3-fluorophenyl) boronic acid (11.4 g, 81.1 mmol) were mixed in DCM (200 mL) and the reaction was stirred at room temperature for 3 days. The solid was filtered off and the filtrate was washed with water several times. The organic layer was dried, concentrated and purified on silica gel to afford 6.3 g of desired product JW-2c in 38% yield. ¹H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.54-7.47 (m, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.20-7.04 (m, 1H) ppm. ESI-MS m/z calc. 240.96509. found 242.27; (M+1)+; Retention time: 0.75 minutes.

Preparation of (1-(3-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine) (Compound 406)

Sodium t-butoxide (95 mg, 0.99 mmol), t-BuXPhos Palladacycle (13 mg, 0.019 mmol), 3-bromo-1-(3-fluorophenyl)-1,2,4-triazole JW-2c (120 mg, 0.49 mmol) and 3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline JW-1b (122 mg, 0.49 mmol) were mixed in t-BuOH (2 mL) and the reaction was degassed for 20 seconds. The reaction was stirred at 60 degrees for 1 hr. The reaction was cooled to room temperature and diluted with 2 ml water. The reaction was extracted with DCM and purified on normal phase (4 gram column, Hex: EtOAc, 10-100%) to afford 83.2 mg (37%) of desired product. ¹H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.11 (s, 1H), 7.79-7.66 (m, 2H), 7.62-7.52 (m, 1H), 7.24-7.04 (m, 2H), 6.88 (s, 1H), 6.31 (s, 1H), 4.57 (t, J=6.5 Hz, 2H), 3.45 (p, J=6.3 Hz, 1H), 3.27-3.12 (m, 4H), 2.47-2.38 (m, 4H), 2.23 (s, 3H) ppm. ESI-MS m/z calc. 408.2074. found 409.45; (M+1)+; Retention time: 0.65 minutes.

Example 3 Preparation of 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 386)

Preparation of 3-bromo-1-(3,4-difluorophenyl)-1,2,4-triazole (JW-3c)

Diacetoxycopper (18.4 g, 101.4 mmol), bromo-triazole (10 g, 67.6 mmol), and 4A molecular sieves (250 mg, 0.33 mmol) were mixed in DCM, to which 4-difluorophenyl)boronic acid (14.9 g, 94.6 mmol), pyridine (10.9 mL, 135.2 mmol) was added. The mixture was stirred at RT under air for 3 days. LCMS showed that no starting material remaining and desired product was formed. The reaction was filtered and the solid was washed with additional DCM (200 ml). The combined organic layer was concentrated with silica gel and dry-loaded to purify on silica gel (240 grams column, 10-90% ethyl acetate:hexanes) to afford 10.5 g (60%) of desired product JW3-c. ¹H NMR (400 MHz, DMSO-D6) δ 9.30 (s, 1H), 8.08-7.96 (m, 1H), 7.77-7.62 (m, 2H) ppm. ESI-MS m/z calc. 258.95566. found 260.32; (M+1)+; Retention time: 0.96 minutes.

Preparation of (1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-vi)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine) (Compound 386)

Sodium t-butoxide (69 mg, 0.72 mmol), t-BuXphos Palladacycle (12 mg, 0.02 mmol), 3-bromo-1-(3,4-difluorophenyl)-1,2,4-triazole JW-3c (120 mg, 0.46 mmol) and 3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline JW-1b (114 mg, 0.46 mmol) were mixed in t-BuOH (2 mL) and the reaction was degassed for 20 seconds. The reaction was stirred at 60 degrees for 1 hour. The reaction was cooled to room temperature and diluted with 2 ml water. The reaction was extracted with DCM (10 ml) and purified on normal phase (4 grams column, Hex: EtOAc, 10-100%) to afford 73 mg (35%) of desired product cmpd 386. ¹H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.05 (s, 1H), 8.18-7.81 (m, 1H), 7.81-7.53 (m, 2H), 7.13 (s, 1H), 6.88 (s, 1H), 6.31 (s, 1H), 4.57 (t, J=6.5 Hz, 2H), 4.53-4.39 (m, 2H), 3.45 (p, J=6.2 Hz, 1H), 3.24-3.10 (m, 4H), 2.46-2.37 (m, 4H), 2.23 (s, 3H) ppm. ESI-MS m/z calc. 426.19797. found 427.41. (M+1)+; Retention time: 0.66 minutes.

Example 4 Preparation of 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 437)

Preparation of 3-bromo-1-(2,5-difluorophenyl)-1,2,4-triazole (JW-4c)

Combined 3-bromo-1H-1,2,4-triazole (29.6 g, 200 mmol), 1,2,4-trifluorobenzene (79.3 g, 62.70 mL, 600.0 mmol) and potassium carbonate (27.6 g, 200.0 mmol) in 500 mL of DMF and heated to 100°-110° for 22 hours. The mixture was cooled and DMF removed under vacuum to dryness. 250 mL of water was added and the organics extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude mixture was purified on silica gel (220 grams column, 10-50% Ethyl acetate:Hexanes) to afford 13 g (25%) of product JW-4c as off white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.10 (d, J=2.0 Hz, 1H), 7.77 (ddd, J=8.9, 5.9, 3.2 Hz, 1H), 7.65 (ddd, J=10.4, 9.3, 4.8 Hz, 1H), 7.52-7.41 (m, 1H) ppm. ESI-MS m/z calc. 258.95566. found 260.01; (M+1)+; Retention time: 0.79 minutes.

Preparation of 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 437)

Sodium t-butoxide (86 mg, 0.90 mmol), t-BuXphos Palladacycle (12 mg, 0.02 mmol), 3-bromo-1-(2,5-difluorophenyl)-1,2,4-triazole JW-4c (164 mg, 0.60 mmol) and 3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline (JW-1b) (154 mg, 0.62 mmol) were mixed in t-BuOH (2.0 mL) and the reaction was degassed with N2 for 30 seconds. The reaction was heated at 60 degrees for 3 hours and the LCMS indicated that the reaction was complete. The reaction was cooled to room temperature and water was added to quench the reaction. Brine was added, the reaction was extracted with DCM and the organic layer was dried and concentrated in vacuo. The crude product was purified on reverse phase (12 grams, 10-90% water:acetonitrile) and the desired fractions were collected, neutralized with aq. NaHCO3 and extracted with EtOAc to afford 85 mg (32%) of free base desired product cmpd 437. ¹H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 7.69 (ddd, J=9.2, 6.0, 3.2 Hz, 1H), 7.67-7.48 (m, 1H), 7.40-7.23 (m, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 6.31 (s, 1H), 4.57 (t, J=6.5 Hz, 2H), 4.47 (t, J=6.0 Hz, 2H), 3.58-3.40 (m, 1H), 3.23-3.00 (m, 4H), 2.45-2.31 (m, 4H), 2.22 (s, 3H) ppm. ESI-MS m/z calc. 426.19797. found 427.45; (M+1)+; Retention time: 0.64 minutes.

Example 5 Preparation of N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-phenyl-1, 2,4-triazol-3-amine (Compound 247)

Preparation of 3-bromo-1-phenyl-1H-1,2,4-triazole (DXM-1A)

To a suspension of 3-bromo-1H-1,2,4-triazole (10 g, 67.6 mM) and phenylboronic acid (16.5 g, 135.2 mM) in 500 mL of DCM, was added the following: pyridine; (10.9 mL, 10.7 g, 135.2 mM), copper (II) acetate; (18.4 g, 101.5 mM) and powdered 4A molecular sieves (45 g). The resulting blue colored suspension was stirred at room temperature for 10 days open to the air. Additional DCM (500 mL) was added to the reaction and the mixture filtered through a pad of diatomaceous earth, washing the cake with DCM, 10% MeOH/DCM, and finally DCM. The filtrates were collected and concentrated under reduced pressure to provide a viscous residue, which was partitioned between ethyl acetate and 1N HCl. The organic phase was washed with water (2×), brine (1×) then dried over anhydrous sodium sulphate. Suction filtered the organic layer to remove particulates and evaporated under reduced pressure to give the crude product which was purified on CombiFlash (240 g column) SiO₂ eluting with 25% ethyl acetate/heptanes. Combined clean fractions and reduced the volume of the fractions under reduced pressure until crystals formed. Isolated crystals via suction filtration, washed with additional heptanes and air dried to yield 3-bromo-1-phenyl-1H-1,2,4-triazole as a white crystalline solid (5.1 g, 34% yield). ¹H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.92-7.79 (m, 2H), 7.58 (dd, J=11.3, 4.5 Hz, 2H), 7.51-7.41 (m, 1H) ppm. ESI-MS m/z calc. 222.9745. found 224.0; (M+1)+; Retention time: 0.75 minutes.

Preparation of 1-methyl-3-nitro-5-(4-N-methylpiperazin-1-yl)benzene (DXM-1a)

3-Bromo-5-nitro-toluene, (20.0 g, 93 mM) and 1-methylpiperazine, (11.5 mL, 10.2 g, 102 mM) were placed into a 500 mL round bottom flask and dissolved in 250 mL of dry tert-butanol and purged with N2 for 10 minutes. The solution was warmed with a heat gun several times to prevent solidification during the nitrogen purge. During the N2 purge, added chloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]palladium(II), min. 98% [t-BuXPhos Palladacycle] (1.5 g, 2.32 mM) followed by sodium tert-butoxide; (13.4 g, 139.0 mM) and the reaction was allowed to stir at 40° C. under nitrogen for one hour. Upon addition of the base, the reaction turned dark and the solution became homogeneous, with subsequent precipitation of a white solid. The solvent was partially removed under reduced pressure and the residue partitioned between ethyl acetate and water; the organic phase washed with brine, dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure. Material was purified on SiO2 with a 0-100% gradient of ethyl acetate to 10% methanol/ethyl acetate as eluent. Material was recrystallized in methyl t-butyl ether to give a medium yellow powder. The mother liquor was evaporated under pressure and re-purified on SiO2 with a 0-100% gradient of dichloromethane to 10% methanol/dichloromethane as the eluent. This material was combined with the first crop and recrystallized from boiling methyl t-butyl ether giving 12 g (52%) of DXM-1a as a medium yellow powder. ¹H NMR (400 MHz, CDCl3) δ 7.53 (d, J=1.8 Hz, 1H), 7.48 (s, 1H), 7.00 (s, 1H), 3.38-3.19 (m, 4H), 2.66-2.49 (m, 4H), 2.39 (s, 3H), 2.36 (d, J=2.0 Hz, 3H) ppm. ESI-MS m/z calc. 235.13. found 236.0; (M+1)+; Retention time: 0.55 minutes.

Preparation of 3-methyl-5-(4-N-methylpiperazin-1-yl)aniline (DXM-1b)

1-Methyl-4-(3-methyl-5-nitro-phenyl) piperazine (DXM-1a, 25 g, 106 mM) was dissolved/suspended in 500 mL of methanol and placed under carbon dioxide before adding 6 g of 10% palladium on carbon (Degussa type, 50% water) to the vessel. Reaction was placed under a hydrogen atmosphere at 50 psi for 14 hours. Note: the initial dark yellow color changes to a light tan solution. The reaction mixture was pulled through a pad of diatomaceous earth, washed with methanol and the solvent was removed under reduced pressure to afford 22 g (70%) of DXM-1b as a tan oil. ¹H NMR (400 MHz, CDCl3) δ 7.48-7.17 (m, 1H), 6.20 (s, 1H), 6.14-5.97 (m, 2H), 3.27-3.07 (m, 4H), 2.69-2.52 (m, 4H), 2.36 (s, 3H), 2.22 (s, 3H) ppm. ESI-MS m/z calc. 205.1579. found 206.0; (M+1)+; Retention time: 0.26 minutes.

Preparation of N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-N-phenyl-1,2,4-triazol-3-amine (Compound 247)

3-bromo-1-N-phenyl-1,2,4-triazole (DXM-1A) (18 g, 80.4 mM, and 3-methyl-5-(4-methylpiperazin-1-yl)aniline; (18.2 g, 88.4 mM) were dissolved into dry tert-butanol (500 mL) and purged with N2 for several minutes. Near the end of the purge, chloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl) [2-(2-aminoethyl)phenyl]palladium(II), min. 98% [t-BuXPhos Palladacycle], (1.5 g, 2.01 mM) and sodium tert-butoxide; (12 g, 121 mM) were added sequentially. The reaction was placed under N₂, stirred and heated at 40° C. for 60 min. Note: a gradual colour change from initial light tan solution to pale yellow suspension was observed and the reaction becomes quite viscous. The reaction was deemed complete by HPLC. Approximately 200 mL of solvent was removed under reduced pressure and the mixture was poured into 2 L of water with stirring. The precipitate was collected via suction filtration and washed with water containing a small amount of sodium carbonate. The wet cake was transferred to a round bottom with methanol and solvents were evaporated under reduced pressure. Dissolved this crude material into dichloromethane and added brine and some saturated sodium carbonate solution (pH 10) and split the layers. The organic phase was dried with anhydrous sodium sulphate and the solvent was removed under reduced pressure to give a light tan solid which was recrystallized from boiling CH3CN (100 mL) and let stand overnight under a nitrogen atmosphere. Isolated crystals via suction filtration and washed with cold CH3CN. A second crop was obtained and kept separate. Main material was recrystallized again from 100 mL of boiling CH3CN, isolated via suction filtration and washed with cold CH3CN. Material was dissolved into DCM and pulled through a 100 uM filter then treated with 2M hydrogen chloride in Et2O (32 mL, 1.1 equiv). The solvents were partially removed under reduced pressure, diluted with hexanes and the resulting precipitate was isolated via suction filtration. Washed with more hexanes and dried under high vacuum to constant weight to yield 20.7 g (64%) of cmpd 247 as the HCl salt and as a white powder. ¹H NMR (400 MHz, CDCl3) δ 10.81 (s, 1H), 9.31 (s, 1H), 9.08 (s, 1H), 7.84 (dd, J=8.6, 1.0 Hz, 2H), 7.55 (dd, J=8.4, 7.6 Hz, 2H), 7.35 (t, J=7.4 Hz, 1H), 7.20 (s, 1H), 6.95 (s, 1H), 6.37 (s, 1H), 3.73 (d, J=11.3 Hz, 2H), 3.50 (d, J=10.8 Hz, 2H), 3.29-3.00 (m, 4H), 2.81 (d, J=4.7 Hz, 3H), 2.24 (s, 3H) ppm. ESI-MS m/z calc. 348.20624. found 349.0; (M+1)+; Retention time: 0.59 minutes.

Example 6 Preparation of 1-(3-fluoro-5-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 323)

Preparation of 3-bromo-1-(3-fluoro-5-methylphenyl)-1H-1,2,4-triazole (HG-3a)

To a 100 ml flask was added 3-bromo-1H-1,2,4-triazole (739.8 mg, 5 mmol), CuI (95.2 mg, 0.50 mmol) and Cs₂CO₃ (1.629 g, 5.0 mmol) and the flask was evacuated then backfilled with N₂ before adding DMSO (5 mL) and 1-fluoro-3-iodo-5-methyl-benzene (590.1 mg, 2.50 mmol). The reaction mixture was heated at 100° C. for 20 h at which time LCMS indicated the major peak was desired product. To the reaction mixture was added EtOAc, the mixture was filtered through celite and to the filtrate was added brine. The organic phase was dried over MgSO4, filtered, evaporated to dryness and purified on an Isco 40 g silica gel column eluting with heptanes and ethyl acetate to afford 3-bromo-1-(3-fluoro-5-methyl-phenyl)-1,2,4-triazole HG-3a (170 mg, 26.6%). ¹H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.23 (dt, J=9.0, 2.0 Hz, 1H), 6.97 (d, J=9.1 Hz, 1H), 2.46 (s, 3H)ppm. ESI-MS m/z calc. 254.98074. found 257.97; (M+1)⁺; Retention time: 0.81 minutes.

Preparation of 1-(3-fluoro-5-methylphenyl)-N-(3-methyl-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (Compound 323)

To a t-BuOH (1.69 mL) solution of 3-bromo-1-(3-fluoro-5-methyl-phenyl)-1,2,4-triazole HG-3a (110 mg, 0.43 mmol) and 3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline JW-1b (117 mg, 0.473 mmol) was added t-BuXPhos Palladacycle (14 mg, 0.022 mmol) and t-BuOK (145 mg, 1.29 mmol), the reaction mixture stirred at 85° C. for 1 h before LCMS indicated the major peak was desired product. To the reaction mixture was added EtOAc and brine, the organic phase was dried over MgSO₄, filtered, concentrated down and purified by an Isco 150 g Gold C18 column eluting with H2O/CH3CN/TFA. The product fractions were extracted with EtOAc, the organic phase dried over MgSO₄, filtered and concentrated to dryness to afford 1-(3-fluoro-5-methylphenyl)-N-(3-methyl-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-3-amine, cmpd 323 (89 mg 48% yield). ¹H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.79 (s, 1H), 6.60 (s, 1H), 6.42 (s, 1H), 4.80-4.62 (m, 4H), 3.67-3.47 (m, 1H), 3.39-3.22 (m, 4H), 2.61-2.49 (m, 4H), 2.45 (s, 3H), 2.35 (s, 3H) ppm. ESI-MS m/z calc. 422.22305. found 423.3; (M+1)⁺; Retention time: 0.62 minutes.

Example 7 Preparation of 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 107)

Preparation of 1-(3-ethyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine (YL-1a)

To a 250 mL round bottom flask with stirrer and reflux condenser was added 1-bromo-3-ethyl-5-nitro-benzene (10 g, 42.2 mmol), 1-(oxetan-3-yl)piperazine (Pharmablock, 6.96 g, 48.5 mmol) and cesium carbonate (27.47 g, 84.3 mmol) in 1,4-dioxane (116 mL). The reaction mixture was purged with N₂ for 5 min. To the mixture was added Pd₂(dba)₃ (772 mg, 0.84 mmol) and t-BuXPhos Palladacycle (804 mg, 1.69 mmol) and the resultant mixture was again purged with nitrogen for 5 minutes. The mixture was warmed to 105° C. and refluxed at this temperature for 18 h. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate:DCM (1:1, 500 mL), filtered through a florisil-bed and the bed washed with ethyl acetate:DCM (1:1, 4×500 ml). The combined filtrates were concentrated under reduced pressure to dryness. ISCO purification (80 g silica; 20% to 50% to 90% of EtOAc in hex) gave 1-(3-ethyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine YL-1a (5.76 g, 47%). ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.49 (m, 2H), 7.04 (s, 1H), 4.70 (dt, J=12.3, 6.4 Hz, 4H), 3.67-3.51 (m, 1H), 3.42-3.22 (m, 4H), 2.71 (q, J=7.6 Hz, 2H), 2.60-2.43 (m, 4H), 1.28 (t, J=7.6 Hz, 3H) ppm. ESI-MS m/z calc. 291.16. found 292.13; (M+1)+; Retention time: 0.63 minutes.

Preparation of 3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline (YL-1b)

To Pd on C, wet, Degussa (631 mg, 0.59 mmol) under N₂ was added a solution of 1-(3-ethyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine YL-1a (5.76 g, 19.8 mmol) in EtOAc (80 mL) and MeOH (20 mL) under N₂. The mixture was shaken under H₂ (50 psi) for 2 hr on a Parr apparatus. The reaction mixture was filtered through celite and evaporated to dryness to give 3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline YL-1b (4.7 g, 91%). ¹H NMR (300 MHz, CDCl₃) δ 6.25 (s, 1H), 6.11 (dd, J=3.9, 1.7 Hz, 2H), 4.83-4.57 (m, 4H), 3.58 (dd, J=12.9, 6.3 Hz, 3H), 3.32-3.11 (m, 4H), 2.52 (dt, J=10.0, 6.3 Hz, 6H), 1.22 (t, J=7.6 Hz, 3H) ppm. ESI-MS m/z calc. 261.18. found 262.48; (M+1)+; Retention time: 0.52 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 107)

A mixture of 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole JW-1c (5.55 g, 21.4 mmol), 3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline YL-1b (4.65 g, 17.79 mmol) and sodium t-butoxide (2.22 g, 23.13 mmol) in t-butyl alcohol (100 mL) and dioxane (15 mL) was purged with N2 for 30 min. [2-(2-Aminoethyl)phenyl]-chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (366 mg, 0.53 mmol) was added and the resultant mixture was heated at 55 C.° for 8 h. LCMS showed the desired product with 10% of starting materials remaining. Additional [2-(2-aminoethyl)phenyl]-chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (122 mg, 0.18 mmol) was added and the reaction mixture was heated at 70° C. for another 2 h. The reaction mixture was cooled to RT and diluted with water (300 mL). The slurry was stirred for 2 h, filtered, the solid collected, washed with water (250 mL) and triturated with ether, then MeOH and dried in vacuo to afford 6 g of product. The product was dissolved in MeOH/DCM (1:9) and filtered through Florisil (50 g) columns. The filtrate was evaporated in vacuo to give 5.2 g of desired product. The desired product was dissolved in MeOH/DCM (1:9; 100 mL) then macroporous polystyrene-bound trimecaptotriazine (MP-TMT) (0.64 mmol/g; 5.5 g, 5 equivalents, Biotage #801472) was added and the suspension rotated at 45-50° C. for 4 h. After filtration, the solvent was evaporated to dryness to afford 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine, cmpd 107 (4.7 g, 59%). ¹H NMR (300 MHz, CDCl₃) δ 8.31 (s, 1H), 7.25 (d, J=5.9 Hz, 2H), 7.14 (s, 1H), 6.88-6.74 (m, 2H), 6.69 (s, 1H), 6.46 (s, 1H), 4.89-4.51 (m, 4H), 3.59 (p, J=6.4 Hz, 1H), 3.42-3.22 (m, 4H), 2.65 (q, J=7.6 Hz, 2H), 2.59-2.41 (m, 4H), 1.28 (t, J=7.6 Hz, 3H) ppm. ESI-MS m/z calc. 440.21. found 441.49; (M+1)+; Retention time: 0.69 minutes.

Example 8 Preparation of N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine (Compound 48)

Preparation of 2-(3-bromo-1,2,4-triazol-1-yl)pyrazine

A mixture of K₂CO₃ (29.19 g, 211.2 mmol), 3-bromo-1H-1,2,4-triazole (25 g, 169.0 mmol) and 2-chloropyrazine (19.36 g, 169.0 mmol) in NMP (130 mL) was heated at 125° C. for 6 hrs. The reaction was quenched with water (300 mL) and stirred for 1 h. The solids were collected, washed with water, ether and dried to give 2-(3-bromo-1,2,4-triazol-1-yl)pyrazine (32 g, 83.8%). ¹H NMR (300 MHz, CD₃OD+CDCl₃) δ 9.40-9.05 (m, 2H), 8.70 (d, J=2.5 Hz, 1H), 8.56 (dd, J=2.5, 1.5 Hz, 1H) ppm. ESI-MS m/z calc. 224.97. found 226.29; (M+1)+; Retention time: 0.75 minutes.

Preparation of 1-(3-ethyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine (YL-1a)

To a 250 mL RB flask with stirrer and reflux condenser was added 1-bromo-3-ethyl-5-nitro-benzene (10 g, 42.16 mmol), 1-(oxetan-3-yl)piperazine (6.96 g, 48.48 mmol) and cesium carbonate (27.47 g, 84.32 mmol) in 1,4-dioxane (116 mL). The reaction mixture was purged with N₂ for 5 min. To above mixture was added Pd₂(dba)₃ (772 mg, 0.84 mmol) and X-PHOS (804 mg, 1.69 mmol) and the resultant mixture was degassed by bubbling in a stream of nitrogen for 5 minutes. The resulting reaction mixture was heated to 105° C. and refluxed at this temperature for 18 h. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate:DCM (1:1, 500 mL), filtered through a florisil-bed and the bed washed with ethyl acetate:DCM (1:1, 4×500 ml). The combined filtrates were concentrated under reduced pressure to dryness and then purified on an ISCO column (80 g silica) eluting with 20% to 50% to 90% of EtOAc in hex) to give 1-(3-ethyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine, YL-1a (5.76 g, 47%). ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.49 (m, 2H), 7.04 (s, 1H), 4.70 (dt, J=12.3, 6.4 Hz, 4H), 3.67-3.51 (m, 1H), 3.42-3.22 (m, 4H), 2.71 (q, J=7.6 Hz, 2H), 2.60-2.43 (m, 4H), 1.28 (t, J=7.6 Hz, 3H) ppm. ESI-MS m/z calc. 291.16. found 292.13; (M+1)+; Retention time: 0.63 minutes.

Preparation of 3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline (YL-1b)

To Pd on C, wet, Degussa (631.2 mg, 0.59 mmol) under N₂ was added a solution of 1-(3-ethyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine (5.76 g, 19.77 mmol) in EtOAc (80 mL) and MeOH (20 mL) under N₂. The mixture was shaken on a Parr apparatus under H₂ (50 psi) for 2 h. The reaction mixture was filtered through celite and evaporated in vacuo to give 3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline YL-1b (4.7 g, 91.0%). ¹H NMR (300 MHz, CDCl₃) δ 6.25 (s, 1H), 6.11 (dd, J=3.9, 1.7 Hz, 2H), 4.83-4.57 (m, 4H), 3.58 (dd, J=12.9, 6.3 Hz, 3H), 3.32-3.11 (m, 4H), 2.52 (dt, J=10.0, 6.3 Hz, 6H), 1.22 (t, J=7.6 Hz, 3H) ppm. ESI-MS m/z calc. 261.18. found 262.48; (M+1)+; Retention time: 0.52 minutes.

Preparation of N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine (Compound 48)

A mixture of 2-(3-bromo-1,2,4-triazol-1-yl)pyrazine (1.30 g, 5.74 mmol), 3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline YL-1b (1.25 g, 4.78 mmol) and sodium t-butoxide (598 mg, 6.22 mmol) in butan-1-ol (30 mL) and dioxane (10 mL) was purged with N₂ for 30 min. t-BuXPhos Palladacycle (131 mg, 0.19 mmol) was added and the resultant mixture was heated at 55° C. for 8 h, then at 70° C. for another 2 h. The reaction mixture was cooled to RT and diluted with water (300 mL). The slurry was stirred for 2 h. The solids were collected, washed with water (250 mL) and triturated with ether, then MeOH and dried in vacuo to afford 3 g of pure product. The above product in MeOH/DCM (1:9) was filtered through a Florisil (20 g) column and the combined solvents were evaporated in vacuo to give 2 g of desired product. The above product was dissolved in MeOH/DCM (1:9; 100 mL) and treated with 5 equivalents of MP-TMT (0.64 mmol/g) and rotated at 45˜50° C. for 4 h. After filtration, the excess solvent was pumped down to afford N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine, cmpd 48 (2.12 g, 52%). ¹H NMR (300 MHz, CDCl₃) δ 9.18 (d, J=1.3 Hz, 1H), 8.93 (s, 1H), 8.57 (d, J=2.5 Hz, 1H), 8.41 (dd, J=2.5, 1.5 Hz, 1H), 7.19 (t, J=2.0 Hz, 1H), 6.83 (d, J=10.4 Hz, 2H), 6.48 (s, 1H), 4.82-4.63 (m, 4H), 3.68-3.53 (m, 1H), 3.40-3.25 (m, 4H), 2.65 (q, J=7.6 Hz, 2H), 2.61-2.42 (m, 4H), 1.29 (t, J=7.6 Hz, 3H) ppm. ESI-MS m/z calc. 406.22. found 407.47; (M+1)+; Retention time: 0.67 minutes.

Using the general synthetic scheme outlined in Scheme A and the experimental procedures listed above in Examples 1-8, the following compounds were prepared:

Cmpd No. IUPAC name 38 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 334 5-methyl-N1-[1-(oxetan-3-yl)-4-piperidyl]-N3-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 278 N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 192 N3-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 472 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 309 5-methyl-N1-[1-(oxetan-3-yl)pyrrolidin-3-yl]-N3-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 188 N3-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 113 N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 421 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 231 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 482 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 17 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 97 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 376 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 69 1-(3,4-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 14 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- fluorophenyl)-1,2,4-triazol-3-amine 102 1-(4-fluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 258 1-(3-fluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 183 1-(3,4-difluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 37 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 54 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- methyl-2-pyridyl)-1,2,4-triazol-3-amine 453 N-[3-[4-(3,3-difluorocyclobutyl)piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 237 N-[2,3-dimethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 425 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 216 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 484 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,3,5-trifluorophenyl)-1,2,4-triazol-3-amine 66 2,5-difluoro-4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]benzonitrile 413 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,4,5-trifluorophenyl)-1,2,4-triazol-3-amine 140 2-fluoro-4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]benzonitrile 86 1-(3-methoxyphenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 94 1-(3-methoxyphenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 56 1-(3-fluoro-5-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 395 1-(3-fluoro-5-methoxy-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 397 1-(3-chlorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 141 1-(3-chlorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 187 1-[3-[[ethyl(methyl)amino]methyl]-5-fluoro-phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 390 1-[3-[[ethyl(methyl)amino]methyl]-5-fluoro-phenyl]-N-[3- methyl-5-(4-methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3- amine 255 1-(3-ethyl-5-fluoro-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 206 1-(3-ethyl-5-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 415 1-(3-fluoro-5-isopropoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 223 1-(2-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 373 1-[3-fluoro-5-[2-methoxyethyl(methyl)amino]phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 103 1-[3-(2-ethylpyrrolidin-1-yl)-5-fluoro-phenyl]-N-[3-methyl-5- [4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 41 1-[3-[2-(ethoxymethyl)pyrrolidin-1-yl]-5-fluoro-phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 480 [1-[3-fluoro-5-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]phenyl]pyrrolidin-3-yl]methanol 467 1-[3-fluoro-5-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 318 2-[(3R)-1-[3-fluoro-5-[3-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]anilino]-1,2,4-triazol-1-yl]phenyl]pyrrolidin- 3-yl]propan-2-ol 491 1-[3-fluoro-5-[(2R)-2-(methoxymethyl)pyrrolidin-1- yl]phenyl]-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 287 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 218 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 252 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine 432 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methoxyphenyl)-1,2,4-triazol-3-amine 70 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(p- tolyl)-1,2,4-triazol-3-amine 31 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(p- tolyl)-1,2,4-triazol-3-amine 476 1-(2-fluoro-5-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 338 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-5-methyl-phenyl)-1,2,4-triazol-3-amine 213 N-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 98 N-[3-fluoro-5-(4-methyl-1,4-diazepan-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 203 N-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 109 N-[3-[3-(dimethylamino)pyrrolidin-1-yl]-5-fluoro-phenyl]-1- (3-fluorophenyl)-1,2,4-triazol-3-amine 166 N-[3-fluoro-5-(1,4-oxazepan-4-yl)phenyl]-1-(3-fluorophenyl)- 1,2,4-triazol-3-amine 351 N1-(azetidin-3-yl)-5-fluoro-N3-[1-(3-fluorophenyl)-1,2,4- triazol-3-yl]benzene-1,3-diamine 177 N1-(azetidin-3-yl)-N3-[1-(2,4-difluorophenyl)-1,2,4-triazol-3- yl]-5-fluoro-benzene-1,3-diamine 343 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(1,4-oxazepan-4- yl)phenyl]-1,2,4-triazol-3-amine 28 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(4-methyl-1,4-diazepan- 1-yl)phenyl]-1,2,4-triazol-3-amine 450 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 347 1-(2,4-difluorophenyl)-N-[3-[3-(dimethylamino)pyrrolidin-1- yl]-5-fluoro-phenyl]-1,2,4-triazol-3-amine 283 N-[3-(3-aminoazetidin-1-yl)-5-fluoro-phenyl]-1-(2,4- difluorophenyl)-1,2,4-triazol-3-amine 149 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 306 N-[3-(2,6-dimethylmorpholin-4-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 179 N-[3-methyl-5-(4-methyl-1,4-diazepan-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 337 N-[3-(4-cyclopropyl-1,4-diazepan-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 280 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 1,4-diazepan-1-yl]ethanone 76 1-methyl-4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-one 157 N-[3-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin- 2-yl]-5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 128 N-[3-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin- 2-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 152 N-[3-[(8aR)-4-isobutyl-3,4,6,7,8,8a-hexahydro-1H- pyrrolo[1,2-a]pyrazin-2-yl]-5-methyl-phenyl]-1-phenyl-1,2,4- triazol-3-amine 29 N-[3-[(8aR)-4-isobutyl-3,4,6,7,8,8a-hexahydro-1H- pyrrolo[1,2-a]pyrazin-2-yl]-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 481 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 162 1-(3,5-difluorophenyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 200 7-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin- 3-one 227 7-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3-one 59 [4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-yl]methanol 81 4-[3-[3-methyl-5-(4-methylpiperazin-1-yl)anilino]-1,2,4- triazol-1-yl]benzonitrile 499 3-[3-[3-methyl-5-(4-methylpiperazin-1-yl)anilino]-1,2,4- triazol-1-yl]benzonitrile 428 1-(2-chlorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 317 1-(3,4-difluorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 299 1-(3,4-difluorophenyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 412 1-(3,4-difluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 182 N1-[1-(3-methoxypropyl)-4-piperidyl]-5-methyl-N3-(1- phenyl-1,2,4-triazol-3-yl)benzene-1,3-diamine 142 1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-4-carbonitrile 146 1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-3-carbonitrile 115 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]anilino]- 1-piperidyl]ethanone 479 N-[3-methyl-5-[(1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]phenyl]-1-phenyl-1,2,4-triazol- 3-amine 5 N-[3-chloro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 310 1-(3,5-difluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 169 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 383 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 207 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 411 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3- piperidyl]phenyl]-1,2,4-triazol-3-amine 439 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methylsulfanylphenyl)-1,2,4-triazol-3-amine 463 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methylsulfanylphenyl)-1,2,4-triazol-3-amine 478 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine 303 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine 191 [4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 322 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 522 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 523 1-(3-fluorophenyl)-N-[3-isopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 574 N-[3,5-bis[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 559 1-(3,4-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- propyl-phenyl]-1,2,4-triazol-3-amine 558 1-(2,5-difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)- 1,2,4-triazol-3-amine 573 N-[3,5-bis(4-tert-butylpiperazin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 657 N-[3,5-bis(4-methylpiperazin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 709 N-[3-(4-tert-butylpiperazin-1-yl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 723 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 753 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-pyrazin- 2-yl-1,2,4-triazol-3-amine 854 N-[3-methyl-5-(4-morpholino-1-piperidyl)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 651 N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 833 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 736 1-[3-(difluoromethyl)phenyl]-N-[3-ethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 595 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 725 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-(4-morpholino-1- piperidyl)phenyl]-1,2,4-triazol-3-amine 693 1-[3-(difluoromethyl)phenyl]-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 662 N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 609 N-[3-methyl-5-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]phenyl]-1- (2-pyridyl)-1,2,4-triazol-3-amine 776 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1,4- diazepan-1-yl]phenyl]-1,2,4-triazol-3-amine 818 N-[3-methyl-5-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 637 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1,4- diazepan-1-yl]phenyl]-1,2,4-triazol-3-amine 697 1-(3,5-difluorophenyl)-N-[2,5-dimethyl-3-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 739 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 785 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 863 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 827 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 819 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 784 N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3,4- difluorophenyl)-1,2,4-triazol-3-amine 587 1-(3,5-difluorophenyl)-N-[2-fluoro-3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 808 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(1,4-oxazepan-4- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 659 1-(3,4-difluorophenyl)-N-[3-methyl-5-[3-(1,4-oxazepan-4- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 825 N-[3-methyl-5-[3-(1,4-oxazepan-4-yl)azetidin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 701 1-(3,5-difluorophenyl)-N-[3-(3-morpholinoazetidin-1-yl)-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 642 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 594 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 783 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 803 1-(3,4-difluorophenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 868 N-[3,5-bis(3-morpholinoazetidin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 759 3-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile 734 3-[3-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile 767 1-(3-chloro-4-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 836 1-(3-fluoro-4-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 715 1-(3-chloro-4-methyl-phenyl)-N-[3-ethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 761 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluoro-4-methyl-phenyl)-1,2,4-triazol-3-amine 762 4-[3-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile 687 4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile 829 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- fluoro-3-methyl-phenyl)-1,2,4-triazol-3-amine 780 1-(4-fluoro-3-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 597 1-(3-chloro-4-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 721 1-(3-fluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 606 1-(4-fluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 794 1-[3-(difluoromethyl)phenyl]-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 647 1-(4-fluoro-3-methyl-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 779 1-(3-fluoro-4-methyl-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 622 1-(4-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 641 1-(3,5-difluorophenyl)-N-[3-isopropoxy-2-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 591 1-(3,5-difluorophenyl)-N-[3-isopropoxy-2-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 757 1-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[3-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 754 1-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[3-methoxy-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 624 1-(3-fluoro-4-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 781 1-(3-fluoro-4-methoxy-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 646 1-(3,5-difluoro-4-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 710 1-(4-methoxyphenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 782 1-(3,5-difluoro-4-methoxy-phenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 841 1-(4-methoxyphenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 735 1-(3-fluoro-4-methoxy-phenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1080 5-deuterio-1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 966 N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl- phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 1071 1-(3-fluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine 977 1-(3,4-difluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine 1034 N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine 967 N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl- phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 965 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5- dimethyl-phenoxy]-1-pyrrolidin-1-yl-ethanone 909 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-(oxetan-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 971 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5- dimethyl-phenoxy]azetidin-1-yl]ethanone 1108 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,3,4,5,6-pentadeuteriophenyl)-1,2,4-triazol-3-amine

Compounds of the invention may be prepared as generally outlined in Scheme B, where R², R³, R⁴⁰, R¹⁰⁰, and X¹ are as described for Scheme A. The methods of Scheme B may also be applied to other variations of L¹ with G¹ to G⁵ that bond to the parent molecular moiety through a nitrogen atom.

Example 9A Preparation of N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 486)

Preparation of 3-nitro-1-phenyl-1, 2,4-triazole (RG-1a)

3-nitro-1H-1,2,4-triazole (20 g, 175 mmol) and phenylboronic acid (43 g, 350 mmol) were suspended in 2.4 L of DCM and pyridine (28.4 mL, 27.8 g, 35 mmol) was added followed by copper (II) acetate (32 g, 175 mmol). The blue coloured suspension was stirred at room temperature for 10 days open to the air. The reaction was pulled through a pad of diatomaceous earth and the filter cake washed with DCM, MeOH, and finally DCM. The filtrates were combined and concentrated to a viscous residue which was partitioned between EtOAc and 1N HCl. The organic phase was washed with water and brine, dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified on 800 grams of SiO2 eluting with 0-25% Ethyl Acetate in DCM. The combined pure fractions were concentrated to dryness to yield 3-nitro-1-phenyl-1,2,4-triazole, RG-1a (16 g, 24%). ¹H NMR (300 MHz, Acetone-d6) δ 9.31 (s, 1H), 7.96 (d, J=7.9 Hz, 2H), 7.67 (dd, J=10.3, 5.0 Hz, 2H), 7.61-7.46 (m, 1H) ppm. ESI-MS m/z calc. 190.05. found 191.0; (M+1)+; Retention time: 0.73 minutes.

Preparation of 1-phenyl-1,2,4-triazol-3-amine (RG-1b)

3-nitro-1-phenyl-1,2,4-triazole (16 g, 84.14 mmoles) was dissolved into 250 mL of methanol and placed under an atmosphere of CO2 before adding 10% Palladium on carbon (wet) Degussa type. The reaction was placed under 50 psi of H2 for 3.0 hours in a Parr apparatus. The reaction was pulled through a pad of diatomaceous earth and washed with more MeOH. The solvent was removed under reduced pressure and yielded 1-phenyl-1,2,4-triazol-3-amine, RG-1b (13.3 grams, 89%). ¹H NMR (300 MHz, Acetone-d6) δ 8.58 (s, 1H), 7.78-7.71 (m, 2H), 7.52-7.41 (m, 2H), 7.30 (dt, J=9.0, 4.3 Hz, 1H), 5.10 (s, 2H) ppm. ESI-MS m/z calc. 160.07489. found 160.95; (M+1)+; Retention time: 0.55 minutes.

Preparation of 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-piperazine (RG-1c)

1-Bromo-3-fluoro-5-(trifluoromethyl)benzene (1.52 g, 6.255 mmol) was dissolved in NMP (2.0 mL). Methylpiperazine (1.88 g, 2.08 mL, 18.8 mmol) was added and the vial was sealed. The reaction mixture was stirred overnight at 100° C. then concentrated to an oil. The oil was diluted with DCM (20 mL), washed with 50% saturated sodium bicarbonate, passed through a phase separator, and the organic layer concentrated to dryness to yield 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-piperazine RG-1c (1.731 g, 83%). ¹H NMR (300 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.18 (s, 2H), 3.30-3.16 (m, 4H), 2.46-2.33 (m, 4H), 2.21 (s, 3H) ppm. ESI-MS m/z calc. 322.02924. found 323.03; (M+1)+; Retention time: 0.62 minutes.

Preparation of N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 486)

1-Phenyl-1,2,4-triazol-3-amine, RG-1b (64 mg, 0.4 mmol), sodium tert-butoxide (57.6 mg, 0.6 mmol), t-BuXPhos Palladacycle (29.5 mg, 0.04 mmol), and 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-piperazine RG-1c (129 mg, 0.4 mmol) were weighed into a 20 ml vial. Vacuum was applied to the vial and then flushed with nitrogen three times. Dioxane (2 mL) was added and the mixture stirred in a sealed vial at 90° C. overnight. The crude reaction mixture was diluted with dichloromethane (20 mL), then washed with 50% saturated sodium bicarbonate. The organic layer was passed through a phase separator and concentrated to dryness. The residue was diluted with DMSO (2 mL) and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and TFA as a modifier to yield the product as the TFA salt. The pooled desired pure fractions were concentrated to dryness. The combined fractions with diluted DCM and washed with saturated sodium bicarbonate. The organics were passed through a phase separator, acidified with 2M HCl in diethyl ether, and concentrated to dryness to yield the HCl salt of N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine, cmpd 486 (99 mg, 56%). ¹H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.89-7.79 (d, 2H), 7.56 (m, 4H), 7.38 (t, J=7.4 Hz, 1H), 6.84 (s, 1H), 3.88 (d, J=9.7 Hz, 2H), 3.51 (m, 2H), 3.19 (m, 4H), 2.85 (s, 3H) ppm. ESI-MS m/z calc. 402.17798. found 403.28; (M+1)+; Retention time: 3.08 minutes.

Example 9B Preparation of 1-(3,5-Difluorophenyl)-N-(2-fluoro-5-methyl-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (Compound 691)

Preparation of 1-(3-bromo-2-fluoro-5-methylphenyl)-4-(oxetan-3-yl)piperazine (PC-1a)

A 50 ml round-bottomed two-necked flask was charged with: 1,3-dibromo-2-fluoro-5-methyl-benzene (1.81 g, 6.76 mmol), 1-(oxetan-3-yl)piperazine (970 mg, 6.75 mmol), BINAP (168 mg, 0.270 mmol), cesium carbonate (4.40 g, 13.5 mmol), Pd₂(dba)₃ (124 mg, 0.135 mmol) and 1,4-dioxane (11 mL) under nitrogen and then heated at reflux overnight. The reaction mixture was filtered through Celite with the aid of EtOAc and then concentrated. Purification by column chromatography (80 g column; 40-100% EtOAc in heptane) gave product PC-1a (1.2 g, 54%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.06 (dd, J=5.8, 1.3 Hz, 1H), 6.84 (dd, J=7.8, 1.6 Hz, 1H), 4.56 (t, J=6.6 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 3.52-3.40 (m, 1H), 3.11-2.93 (m, 4H), 2.47-2.35 (m, 4H), 2.25 (s, 3H) ppm. ESI-MS m/z calc. 328.05865, (M+1) found 329.11.

Preparation of 1-(3,5-Difluorophenyl)-N-(2-fluoro-5-methyl-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (Compound 691)

A 20 mL scintillation vial was charged with 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine RG-9B (281 mg, 1.43 mmol), 1-(3-bromo-2-fluoro-5-methyl-phenyl)-4-(oxetan-3-yl)piperazine PC-1a (471 mg, 1.43 mmol), Xphos palladacycle (Strem 46-0268) (53 mg, 0.0717 mmol), sodium tert-butoxide (275 mg, 2.86 mmol) and tBuOH (12 mL) under nitrogen and stirred on a heating block set to 100° C. for 2 h. Brine and EtOAc were added and the layers separated. The organics were concentrated, the crude residue was purified by column chromatography (80 g column; 50-100% EtOAc in heptane) and the relevant fractions concentrated. The impure material was sonicated in the presence of EtOAc and filtered off. The solid was collected and sonicated in the presence of MeOH to give product (185 mg, 29%) as a white solid after filtration. ¹H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.81 (d, J=1.7 Hz, 1H), 7.65-7.55 (m, 2H), 7.50 (d, J=5.8 Hz, 1H), 7.25 (tt, J=9.3, 2.3 Hz, 1H), 6.44 (d, J=5.9 Hz, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.47 (t, J=6.1 Hz, 2H), 3.52-3.44 (m, 1H), 3.06-2.97 (m, 4H), 2.43 (s, 4H), 2.27 (s, 3H) ppm. ESI-MS m/z calc. 444.18854. found 445.33; (M+1).

Using the general synthetic scheme outlined in Scheme B and the experimental procedures listed above in Example 9A or 9B, the following compounds were prepared:

Cmpd No. IUPAC Name 269 1-(4-fluorophenyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 272 1-(3-fluorophenyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 167 1-(4-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 158 N-(3-fluoro-5-morpholino-phenyl)-1-(3-fluorophenyl)-1,2,4- triazol-3-amine 435 1-(3-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 394 N-(3-fluoro-5-morpholino-phenyl)-1-(4-fluorophenyl)-1,2,4- triazol-3-amine 441 N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 356 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 241 N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 181 N-(3-fluoro-5-morpholino-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 497 1-(2,4-difluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl- phenyl)-1,2,4-triazol-3-amine 321 1-(2,4-difluorophenyl)-N-(3-fluoro-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 190 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 99 1-(3,4-difluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl- phenyl)-1,2,4-triazol-3-amine 440 1-(3,4-difluorophenyl)-N-(3-fluoro-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 49 N-(3-fluoro-5-morpholino-phenyl)-1-(2-fluorophenyl)-1,2,4- triazol-3-amine 83 1-(2-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 43 1-(3,4-difluorophenyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 27 1-(3-fluorophenyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 374 1-(3,5-difluorophenyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 186 4-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile 372 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-(p-tolyl)-1,2,4- triazol-3-amine 281 3-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile 212 2-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile 335 N-(3-chloro-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 426 N-(3-chloro-5-morpholino-phenyl)-1-(3,5-difluorophenyl)- 1,2,4-triazol-3-amine 168 N-(3-bromo-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 346 N-(3-bromo-5-morpholino-phenyl)-1-(3,5-difluorophenyl)- 1,2,4-triazol-3-amine 392 N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 246 N-[3-chloro-5-[4-(methoxymethyl)-1-piperidyl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 85 N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-(2-fluoro-4- pyridyl)-1,2,4-triazol-3-amine 431 N-[3-methyl-5-[4-[(3-methyloxetan-3-yl)methyl]piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 330 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 468 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 344 1-(3,5-difluorophenyl)-N-[3-methylsulfonyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 16 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 361 1-(3-fluorophenyl)-N-[3-methylsulfonyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 417 1-(2,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 110 N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4- triazol-3-amine 380 N-(3-chloro-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4- triazol-3-amine 45 N-(3-methyl-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 336 N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4- triazol-3-amine 175 1-(3-fluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 130 1-(3,5-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]- 5-(trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 1 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-4-amine 295 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]oxazolidin-2-one 501 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 502 4-methyl-6-(3-morpholinoazetidin-1-yl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-2-amine 512 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 517 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]oxazolidin-2-one 524 4-(difluoromethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 525 4-(difluoromethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 526 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1- phenyl-1,2,4-triazol-3-yl)pyridin-2-amine 843 6-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-N-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-pyridin-2-amine 581 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 751 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2R)-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 623 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 577 1-(3,4-difluorophenyl)-N-[3-ethyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 820 1-(3,5-difluorophenyl)-N-[2,5-dimethyl-3-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 691 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 835 3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile 678 3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile 656 3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile 668 3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile 737 3-[[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile 793 3-[[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile 608 3-morpholino-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]benzonitrile 804 N-[3-(difluoromethyl)-5-(3-morpholinoazetidin-1- yl)phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 592 3-[4-(oxetan-3-yl)piperazin-1-yl]-5-[(1-phenyl-1,2,4-triazol- 3-yl)amino]benzonitrile 681 5-methyl-N1,N3-bis(1-phenyl-1,2,4-triazol-3-yl)benzene- 1,3-diamine 813 N-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenoxy]cyclobutyl]acetamide 752 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3- morpholinocyclobutoxy)phenyl]-1,2,4-triazol-3-amine 663 1-(3,5-difluorophenyl)-N-[3-methyl-5-[6-methyl-4-(oxetan- 3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 629 1-(3,5-difluorophenyl)-N-[3-methyl-5-[5-methyl-4-(oxetan- 3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 708 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-methyl-4-(oxetan- 3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 750 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2R)-2-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 667 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-2-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 1058 N-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]cyclopropanecarboxamide 910 1-cyclobutyl-3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]urea 908 N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine 1085 N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 923 [3-acetoxy-2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-2-fluoro-5-methyl-phenyl]piperazin-1- yl]propyl]acetate 989 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]piperazin-1-yl]propane-1,3-diol 999 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- tetrahydropyran-3-yloxy-pyridin-2-amine 980 6-(cyclopropylmethoxy)-N-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-4-methyl-pyridin-2-amine 1069 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (oxetan-3-ylmethoxy)pyridin-2-amine 998 1-(3,4-difluorophenyl)-N-[2-fluoro-5-methyl-3-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1022 N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 1100 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,4- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone 1101 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3-fluorophenyl)-1,2,4-triazol-3- amine 1102 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3-fluorophenyl)-1,2,4-triazol-3- amine 1103 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3- fluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone 1104 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[[1-(3-fluorophenyl)-1,2,4-triazol-3- yl]amino]phenyl]piperazin-1-yl]methanone 1105 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3- amine 1106 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3- amine 1107 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]methanone

Compounds of the invention may be prepared as generally outlined in Scheme C, where R, R¹, R⁴⁰, and R¹⁰⁰ are as described for Scheme A. The methods of Scheme C may also be applied to other variations of L¹ with G¹ to G⁵ that bond to the parent molecular moiety through a nitrogen atom and the G¹ to G⁵ group contains an available nitrogen for reductive amination or acylation.

Example 10 Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 33)

Preparation of tert-butyl 4-(3-methyl-5-nitro-phenyl)piperazine-1-carboxylate (JW-5a)

To a 250 ml RBF was added 1-bromo-3-methyl-5-nitro-benzene (7.6 g, 35.2 mmol) and tert-butyl piperazine-1-carboxylate (6.68 g, 35.8 mmol) into 2-methylpropan-2-ol (50 mL). To this mixture was added sodium 2-methylpropan-2-olate (8.4 g, 87.4 mmol) and chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (231 mg, 2.171 mmol). The mixture was degassed under nitrogen for 1 minute. The reaction was stirred and heated at 75° C. overnight. The reaction was then diluted with EtOAc (100 ml) and 10 ml of water was added slowly. This mixture was washed with water (100 ml) and brine (200 ml). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude material was purified on a short plug of silica gel (50 g) using 1:1 EtOAc:Hexanes to afford 6.1 g (48%) of desired product JW-5a as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=2.5 Hz, 2H), 7.02 (s, 1H), 3.68-3.55 (m, 4H), 3.31-3.14 (m, 4H), 2.42 (s, 3H), 1.51 (s, 9H) ppm. ESI-MS m/z calc. 321.16885. found 322.1; (M+1)+; Retention time: 0.84 minutes.

Preparation of tert-butyl 4-(3-amino-5-methyl-phenyl)piperazine-1-carboxylate (JW-5b)

Catalyst palladium on carbon (10% WT, Degussa, 120 mg, 1.1 mmol) was added to a 250 ml RBF under N2 and EtOH (50 mL) was added. tert-Butyl 4-(3-methyl-5-nitro-phenyl)piperazine-1-carboxylate JW-5a (2.9 g, 9.1 mmol) was added and the reaction was stirred under H2 overnight. The catalyst was filtered and the solvent was removed in vacuo to give 2.45 g of desired product JW-5b. ¹H NMR (400 MHz, CDCl3) δ 6.19 (s, 1H), 6.13-6.03 (m, 2H), 3.55 (dd, J=10.7, 5.6 Hz, 6H), 3.16-3.02 (m, 4H), 2.22 (s, 3H), 1.48 (s, 9H) ppm. ESI-MS m/z calc. 291.19467. found 292.45; (M+1)+; Retention time: 0.6 minutes.

Preparation of tert-butyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate (JW-5d)

3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole JW-1c (850 mg, 3.3 mmol), sodium 2-methylpropan-2-olate (630 mg, 6.6 mmol) and chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (52 mg, 0.49 mmol) and tert-butyl 4-(3-amino-5-methyl-phenyl)piperazine-1-carboxylate JW-5b (1.2 g, 3.5 mmol) were mixed in 2-methylpropan-2-ol (10 ml) and the reaction was degassed under nitrogen for 20 seconds. The reaction was capped in a reaction tube (5 ml) and the reaction heated at 75 degrees overnight. The reaction was cooled to room temperature and to the mixture was added 1 ml of MeOH. The solvent was removed in vacuo and the crude was adsorbed onto 5 grams of silica gel and purified on silica gel (12 gram column, Hexanes:EtOAc 30-100%) to afford 732 mg (50%) of desired product JW-5d. ¹H NMR (300 MHz, Acetone-d6) δ 8.92 (s, 1H), 8.34 (s, 1H), 7.57 (dd, J=8.7, 2.3 Hz, 2H), 7.33 (s, 1H), 7.09-6.88 (m, 2H), 6.43 (s, 1H), 3.63-3.49 (m, 4H), 3.25-3.07 (m, 4H), 2.29 (s, 3H), 1.47 (s, 9H) ppm. ESI-MS m/z calc. 470.22418. found 471.0; (M+1)+; Retention time: 0.81 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)-1, 2,4-triazol-3-amine (JW-5e)

tert-Butyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate JW-5d (600 mg, 1.1 mmol) was dissolved in a mixture of DCM (6 mL) and TFA (3.0 ml). The reaction was stirred at room temperature for 2 hours and the LCMS indicated that the reaction was complete. The solvent was removed and the crude was dissolved in DCM (10 mL) and the solution was washed with NaHCO3 (sat. aq., 20 ml) and brine (20 ml). The combined aqueous phase was extracted with DCM (5 ml×5) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 321 mg of desired product JW-5e. ¹H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.26 (s, 2H), 9.19 (s, 1H), 7.63 (dd, J=8.5, 2.1 Hz, 2H), 7.26 (d, J=2.3 Hz, 1H), 7.19 (s, 1H), 6.97 (s, 1H), 6.40 (s, 1H), 3.46-3.31 (m, 4H), 3.24 (s, 4H), 2.25 (s, 3H) ppm. ESI-MS m/z calc. 370.17175. found 371.0. (M+1)+; Retention time: 0.64 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 33)

1-(3,5-Difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)-1,2,4-triazol-3-amine (52 mg, 0.14 mmol) was dissolved in DCE (2 mL). Oxetan-3-one (25 mg, 0.35 mmol) and Na(OAc)₃BH (123 mg, 0.58 mmol) were added to the reaction. The reaction was stirred at room temperature overnight. 1N NaOH (aq., 1 mL) was added and the organic layer was separated and the aqueous layer was extracted with DCM (2 ml). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified on silica gel using DCM:MeOH (0-4%) to afford desired product cmpd 33. ¹H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.28-7.21 (m, 2H), 7.12 (t, J=1.9 Hz, 1H), 6.88-6.68 (m, 3H), 6.46 (d, J=14.4 Hz, 1H), 4.81-4.70 (m, 4H), 3.67-3.48 (m, 1H), 3.33 (dd, J=13.0, 8.2 Hz, 4H), 2.61-2.51 (m, 4H), 2.35 (s, 3H) ppm. ESI-MS m/z calc. 426.19797. found 427.36; (M+1)+; Retention time: 0.65 minutes.

Example 11 Preparation of N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1, 2,4-triazol-3-amine (Compound 118)

Preparation of tert-butyl 4-[3-methyl-5-[(1-phenyl-1, 2,4-triazol-3-yl)amino]phenyl]piperazine-1-carboxylate (JW-6d)

tert-Butyl 4-(3-amino-5-methyl-phenyl)piperazine-1-carboxylate JW-5b (1.9 g, 6.5 mmol), 3-bromo-1-phenyl-1,2,4-triazole (DXM-1A) (1.0 g, 4.49 mmol) were added to t-BuOH (15.0 mL). t-BuXPhos Palladacycle (82 mg, 0.12 mmol) and sodium t-butoxide (631 mg, 6.6 mmol) were added to the reaction mixture. The reaction was degassed with nitrogen for 1 min and heated at 60° C. overnight. The reaction was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL). The solvent was removed under reduced pressure and purified on silica gel (40 g column, 10-90% Hex: EtOAc) to afford 1.21 g (55%) of desired product JW-6d. ¹H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.05 (s, 1H), 7.83 (dd, J=8.6, 1.0 Hz, 2H), 7.62-7.45 (m, 2H), 7.35 (t, J=7.4 Hz, 1H), 7.16 (s, 1H), 6.93 (s, 1H), 6.31 (s, 1H), 3.60-3.37 (m, 4H), 3.20-2.93 (m, 4H), 2.23 (s, 3H), 1.43 (s, 9H) ppm. ESI-MS m/z calc. 434.243. found 435.0; (M+1)+; Retention time: 0.78 minutes.

Preparation of N-(3-methyl-5-piperazin-1-yl-phenyl)-1-phenyl-1,2,4-triazol-3-amine(JW-6e)

tert-Butyl 4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]piperazine-1-carboxylate JW-6d (1.88 g, 4.3 mmol) was dissolved in DCM (20 mL) and HCl (12 mL of a 2M soln in diethyl ether, 24.0 mmol) was added into the reaction. The reaction was stirred at 50 degrees overnight and a solid was generated. The solid was collected by filtration and washed with diethyl ether (20 mL) and dried in vacuo to afford 1.582 g (92%) of desired product JW-6e. ¹H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 9.08 (s, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.35 (t, J=7.4 Hz, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 6.39 (s, 1H), 3.48-3.30 (m, 4H), 3.25 (s, 4H), 2.25 (s, 3H) ppm. ESI-MS m/z calc. 334.19058. found 335.47; (M+1)+; Retention time: 0.64 minutes.

Preparation of N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 118)

N-(3-Methyl-5-piperazin-1-yl-phenyl)-1-phenyl-1,2,4-triazol-3-amine JW-6e (1.42 g, 4.2 mmol) and oxetan-3-one (612 mg, 8.5 mmol) were stirred in DCE (25 mL) at room temperature for 15 mins and Na(OAc)₃BH (2.7 g, 12.7 mmol) was added into the reaction. The reaction was stirred at room temperature for 5 hours and the LCMS indicated that the reaction was completed. 1N NaOH aq. solution (10 ml) was added into the reaction and the reaction was washed with water and extracted with DCM (100 ml×3). The organic layers were combined and dried over Na2SO4 and purified on CombiFlash (40 g column, 10-90% EtOAc:Hexane) to afford 1.02 g (61%) of desired product, cmpd 118. ¹H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.05 (s, 1H), 7.89-7.75 (m, 2H), 7.55 (t, J=8.0 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 7.16 (s, 1H), 6.88 (s, 1H), 6.29 (s, 1H), 4.57 (t, J=6.5 Hz, 2H), 4.49 (t, J=6.0 Hz, 2H), 3.56-3.38 (m, 1H), 3.22-3.09 (m, 3H), 2.47-2.37 (m, 4H), 2.22 (s, 3H) ppm. ESI-MS m/z calc. 390.2168. found 391.5; (M+1)+; Retention time: 0.62 minutes.

Example 12 Preparation of N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 26)

Preparation of 1-bromo[3-(difluoromethyl)phenyl]piperazine (YL-2a)

A mixture of 1-bromo-3-(difluoromethyl)-5-fluoro-benzene (1 g, 4.44 mmol) and 1-cyclopropylpiperazine (2.80 g, 22.22 mmol) was microwaved at 200° C. for 1 h. Pumped down solvent and purified the crude mixture by ISCO purification (40 g silica; 0% to 5% to 30% of MeOH in DCM) to provide 1-[3-bromo-5-(difluoromethyl)phenyl]piperazine (920 mg, 89%). ¹H NMR (300 MHz, CD₃OD) δ 7.20 (s, 1H), 7.09 (s, 1H), 7.05 (d, J=1.0 Hz, 1H), 6.66 (t, J=56.1 Hz, 1H), 3.20 (dd, J=6.2, 4.0 Hz, 4H), 2.98 (dd, J=6.2, 4.1 Hz, 4H) ppm. ESI-MS m/z calc. 290.02. found 291.19; (M+1)+; Retention time: 0.63 minutes.

Preparation of t-Butyl 4-[3-bromo-5-(difluoromethyl)phenyl]piperazine-1-carboxylate (YL-2b)

A mixture of 1-[3-bromo-5-(difluoromethyl)phenyl]piperazine (920 mg, 3.16 mmol) and (tBuO)₂CO (1.03 g, 4.74 mmol) in dichloromethane (15 mL) was stirred at RT for 30 min. The reaction was quenched with MeOH (300 uL), diluted with DCM (15 mL) and washed with water (2×3 mL). The organic layer was filtered through florisil (5 g) and pumped down to dryness. The crude material was purified by ISCO purification (12 g silica; 10% to 100% of EtOAc in hex) to give t-butyl 4-[3-bromo-5-(difluoromethyl)phenyl]piperazine-1-carboxylate YL-2b (830 mg, 67%). ¹H NMR (300 MHz, CDCl₃) δ 7.11 (d, J=0.8 Hz, 2H), 6.94 (s, 1H), 6.55 (t, J=56.3 Hz, 1H), 3.70-3.50 (m, 4H), 3.28-3.12 (m, 4H), 1.50 (s, 9H) ppm. ESI-MS m/z calc. 390.08. found 391.18; (M+1)+; Retention time: 1.01 minutes.

Preparation of t-butyl 4-[3-(difluoromethyl)-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]piperazine-1-carboxylate (YL-2c)

t-Butyl 4-[3-bromo-5-(difluoromethyl)phenyl]piperazine-1-carboxylate YL-2b (160 mg, 0.41 mmol), 1-phenyl-1,2,4-triazol-3-amine RG-1b (79 mg, 0.49 mmol) and sodium t-butoxide (79 mg, 0.82 mmol) were suspended in dioxane (6 mL) and purged with N₂ for several minutes before addition of t-BuXPhos Palladacycle (13 mg, 0.02 mmol). The vial was capped and microwaved at 120° C. for 35 minutes. The reaction was quenched with MeOH (0.5 mL), 1N HCl (800 uL) and diluted with DCM. After filtration through Florisil (5 g), the excess solvent was pumped down in vacuo. ISCO purification (12 g silica; 0% to 10% of MeOH in DCM) gave t-butyl 4-[3-(difluoromethyl)-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]piperazine-1-carboxylate YL-2c (100 mg, 52%). ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 7.72-7.66 (m, 2H), 7.53 (ddd, J=8.3, 5.3, 1.8 Hz, 2H), 7.43-7.35 (m, 2H), 7.30 (s, 1H), 7.15 (s, 1H), 6.80-6.41 (m, 2H), 3.68-3.56 (m, 4H), 3.30-3.19 (m, 4H), 1.52 (s, 9H) ppm. ESI-MS m/z calc. 470.22. found 471.28; (M+1)+; Retention time: 0.93 minutes.

Preparation of N-[3-(difluoromethyl)-5-piperazin-1-yl-phenyl]-1-phenyl-1,2,4-triazol-3-amine (YL-2d)

A mixture of tert-butyl 4-[3-(difluoromethyl)-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]piperazine-1-carboxylate YL-2c (100 mg, 0.21 mmol) and TFA (818 μL, 10.6 mmol) in DCM was stirred at RT for 1 h. LCMS showed the desired product. Pumped down the solvent to dryness. The crude product was dissolved in DCM and filtered through PL-HCO₃ MP SPE (500 mg). The filtrate was evaporated in vacuo to give N-[3-(difluoromethyl)-5-piperazin-1-yl-phenyl]-1-phenyl-1,2,4-triazol-3-amine YL-2d (64 mg, 77%). ¹H NMR (300 MHz, CD₃OD) δ 8.80 (s, 1H), 7.85-7.75 (m, 2H), 7.51 (dd, J=16.5, 8.1 Hz, 3H), 7.36 (dd, J=13.5, 6.0 Hz, 2H), 6.68 (dd, J=64.3, 48.6 Hz, 2H), 3.39 (dd, J=6.5, 3.7 Hz, 4H), 3.26 (dd, J=6.5, 3.6 Hz, 4H) ppm. ESI-MS m/z calc. 370.17. found 371.29; (M+1)+; Retention time: 0.64 minutes.

Preparation of N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 26)

To a solution of N-[3-(difluoromethyl)-5-piperazin-1-yl-phenyl]-1-phenyl-1,2,4-triazol-3-amine YL-2d (120 mg, 0.32 mmol), oxetan-3-one (234 mg, 3.24 mmol) and acetic acid (117 mg, 1.94 mmol) in dichloromethane (6.0 mL) was added NaBH(OAc)₃ (412 mg, 1.94 mmol) and the mixture was stirred for 18 h. The reaction was diluted with DCM and slowly quenched with MeOH and saturated NaHCO₃. After separation, the organic layer was washed with water, saturated NaCl and dried then evaporated in vacuo. The crude material was subjected to ISCO purification (12 g silica; 0% to 5% to 10% of MeOH in DCM) to give N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine, cmpd 26 (107 mg, 74%). ¹H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.73-7.65 (m, 2H), 7.53 (ddd, J=8.3, 5.3, 1.8 Hz, 2H), 7.38 (ddd, J=8.7, 4.6, 1.2 Hz, 2H), 7.17 (s, 1H), 6.86 (s, 1H), 6.63 (dd, J=67.7, 45.7 Hz, 2H), 4.72 (p, J=6.4 Hz, 4H), 3.59 (p, J=6.4 Hz, 1H), 3.41-3.24 (m, 4H), 2.61-2.48 (m, 4H) ppm. ESI-MS m/z calc. 426.20. found 427.41; (M+1)+; Retention time: 0.65 minutes.

Example 13 Preparation of 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 40)

Preparation of t-butyl 4-(3-methyl-5-nitro-phenyl)piperazine-1-carboxylate (YL-3a)

A mixture of 1-bromo-3-methyl-5-nitro-benzene (50 g, 231 mmol), sodium t-butoxide (33.36 g, 347 mmol) and tert-butyl piperazine-1-carboxylate (47.40 g, 255 mmol) in dry t-BuOH (500 mL) was purged with N₂ for 40 min. After the purge, t-BuXPhos Palladacycle (7.54 g, 11.57 mmol) was added and the mixture was heated at 40° C. for 60 min. The reaction was then quenched with MeOH and solvents removed under reduced pressure. The residue was partitioned between EtOAc and water, the organic phase washed with more water, then brine, dried (Na₂SO₄) and removed solvent under reduced pressure. The crude product was purified on SiO2 column (330 g) eluting with a DCM/EtOAc (0-50%) gradient to afford t-butyl 4-(3-methyl-5-nitro-phenyl)piperazine-1-carboxylate YL-3a (40 g, 54%). ¹H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 3.54-3.37 (m, 4H), 3.28-3.17 (m, 4H), 2.37 (s, 3H), 1.42 (s, 9H) ppm.

Preparation of t-butyl 4-(3-amino-5-methyl-phenyl)piperazine-1-carboxylate (YL-3b)

To 10% Pd on C, wet, Degussa (139 mg, 0.13 mmol) under N₂ was added a solution of t-butyl 4-(3-methyl-5-nitro-phenyl)piperazine-1-carboxylate YL-3a (1.4 g, 4.36 mmol) in EtOAc (20 mL) and MeOH (5 mL) and the mixture was shaken under H₂ (50 psi) for 2 hr. The reaction mixture was filtered through Celite and the filtrate pumped down to give t-butyl 4-(3-amino-5-methyl-phenyl)piperazine-1-carboxylate YL-3b (1.25 g, 99%). ¹H NMR (300 MHz, CDCl₃) δ 6.21 (s, 1H), 6.13-6.07 (m, 2H), 3.62-3.50 (m, 4H), 3.18-3.03 (m, 4H), 2.24 (s, 3H), 1.50 (s, 9H) ppm. ESI-MS m/z calc. 291.19. found 292.12; (M+1)⁺; Retention time: 0.64 minutes.

Preparation of t-butyl 4-[3-[[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate (YL-3c)

t-Butyl 4-(3-amino-5-methyl-phenyl)piperazine-1-carboxylate YL-3b (180 mg, 0.62 mmol), 4-(3-bromo-1,2,4-triazol-1-yl)-2-fluoro-pyridine (180 mg, 0.74 mmol) and sodium t-butoxide (119 mg, 1.24 mmol) were suspended in dioxane (4.8 mL) and purged with N₂ for several minutes before addition of the t-BuXPhos Palladacycle (20 mg, 0.03 mmol). The vial was capped and microwaved at 120° C. for 35 minutes. LC/MS showed desired product so the reaction was quenched with MeOH (0.5 mL), 1N HCl (800 uL) and diluted with DCM. After filtration through Florisil (5 g), the excess solvent was removed under reduced pressure then the crude product subjected to ISCO purification (12 g silica; 10% to 50% to 100% of EtOAc in hex) to give t-butyl 4-[3-[[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate YL-3c (73 mg, 26%). ¹H NMR (300 MHz, CD₃OD+CDCl₃) δ 8.84 (s, 1H), 8.24 (d, J=5.7 Hz, 1H), 7.63 (d, J=5.7 Hz, 1H), 7.41 (s, 1H), 7.13 (s, 1H), 6.91 (s, 1H), 6.41 (s, 1H), 3.67-3.49 (m, 4H), 3.26-3.05 (m, 4H), 2.31 (s, 3H), 1.46 (s, 9H) ppm. ESI-MS m/z calc. 453.23. found 454.21; (M+1)⁺; Retention time: 0.81 minutes.

Preparation of 1-(2-fluoro-4-pyridyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)-1, 2,4-triazol-3-amine (YL-3d)

To a solution of t-butyl 4-[3-[[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate YL-3c (73 mg, 0.16 mmol) in DCM (3 mL) was added TFA (620 μL, 8.05 mmol) and the reaction mixture stirred for 2 hr. Pumped down solvent to 1-(2-fluoro-4-pyridyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)-1,2,4-triazol-3-amine YL-3d (50 mg, 88%). ¹H NMR (300 MHz, CDCl₃) δ 8.45 (s, 1H), 8.30 (d, J=5.2 Hz, 1H), 7.45 (d, J=4.6 Hz, 1H), 7.06 (s, 1H), 6.79 (s, 1H), 6.69 (s, 1H), 6.44 (s, 1H), 3.19 (s, 4H), 3.06 (s, 4H), 2.34 (s, 3H) ppm. ESI-MS m/z calc. 353.18. found 354.41; (M+1)⁺; Retention time: 0.62 minutes.

Preparation of 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 40)

To a solution of 1-(2-fluoro-4-pyridyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)-1,2,4-triazol-3-amine YL-3d (50 mg, 0.14 mmol), oxetan-3-one (102 mg, 1.42 mmol) and acetic acid (48 μL, 0.85 mmol) in dichloromethane (2.5 mL) was added NaBH(OAc)₃ (180 mg, 0.85 mmol) carefully and the mixture was stirred for 2 h. LCMS showed desired product so the reaction was diluted with DCM and slowly quenched with MeOH and sat. NaHCO₃ (3 mL). After separation, the organic layer was washed with water, sat NaCl and dried. The organics were concentrated to dryness and the crude material was subjected to ISCO purification (12 g silica; 0% to 5% to 10% of MeOH in DCM) to give 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine, cmpd 40 (50 mg, 82%). ¹H NMR (300 MHz, CDCl₃) δ 8.46 (d, J=6.7 Hz, 1H), 8.32 (d, J=5.6 Hz, 1H), 7.52-7.44 (m, 1H), 7.27 (d, J=1.5 Hz, 1H), 7.08 (s, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.46 (s, 1H), 4.80-4.65 (m, 4H), 3.68-3.54 (m, 1H), 3.38-3.25 (m, 4H), 2.63-2.50 (m, 4H), 2.37 (s, 3H) ppm. ESI-MS m/z calc. 409.20. found 410.28. (M+1)+; Retention time: 0.59 minutes.

Using the general synthetic scheme outlined in Scheme C and the experimental procedures listed above in Examples 10-13, the following compounds were prepared:

Cmpd No. IUPAC Name 458 cyclopropyl-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]methanone 196 ethyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazine-1-carboxylate 350 2,2,2-trifluoroethyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate 137 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydrofuran-3- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 199 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydropyran-3- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 243 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydropyran-4- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 352 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2,2,2-trifluoro-ethanone 290 N-[3-(4-cyclobutylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 434 N-[3-methyl-5-(4-tetrahydrofuran-3-ylpiperazin-1-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 127 N-[3-methyl-5-[4-(2-methyltetrahydrofuran-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 172 N-[3-methyl-5-(4-tetrahydropyran-3-ylpiperazin-1-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 87 N-[3-(4-cyclopentylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 370 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]ethanone 422 methyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazine-1-carboxylate 233 1-[2-(methoxymethyl)phenyl]-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 414 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(o- tolyl)-1,2,4-triazol-3-amine 95 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(thietan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 228 1-(3,5-difluorophenyl)-N-[3-[4-(1,1-dioxothietan-3-yl)piperazin- 1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 159 N-(3-methyl-5-piperazin-1-yl-phenyl)-1-phenyl-1,2,4-triazol-3- amine 77 1-(3,5-difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)- 1,2,4-triazol-3-amine 259 N-[3-methyl-5-(3-methylpiperazin-1-yl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 362 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 21 N-[3-(2,5-dimethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 133 N-[3-(3,4-dimethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 119 1-(3,5-difluorophenyl)-N-[3-(3,4-dimethylpiperazin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 419 N-[3-methyl-5-(2,4,5-trimethylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 292 N-[3-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5- yl]-5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 78 N-[3-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5- yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 219 N-[3-methyl-5-[(1S,4S)-2-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1-phenyl-1,2,4-triazol-3- amine 34 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1S,4S)-2-(oxetan-3-yl)- 2,5-diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3- amine 459 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]phenyl]-1,2,4-triazol-3-amine 185 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-2-(oxetan-3-yl)- 2,5-diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3- amine 93 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-2-one 67 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-(oxetan-3-yl)piperazin-2-one 392 N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-phenyl-1,2,4- triazol-3-amine 85 N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-(2-fluoro-4- pyridyl)-1,2,4-triazol-3-amine 125 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]acetic acid 438 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperidin-3-ol 282 (3R,4R)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-1-(oxetan-3-yl)piperidin-3-ol; (3S,4S)-4-[3- [[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-1-(oxetan-3-yl)piperidin-3-ol 72 ethyl 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]acetate 509 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2-methyl-propanoic acid 530 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(3S)-tetrahydrofuran- 3-yl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 531 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(3R)-tetrahydrofuran- 3-yl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 898 N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine 997 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(3-deuteriooxetan-3-yl)piperazin-1-yl]phenyl]- 1,2,4-triazol-3-amine

Compounds of the invention may be prepared as generally outlined in Scheme D, where R², R³, R¹⁰⁰, and X¹ are as described for Scheme A. The methods of Scheme D may also be applied to other variations of L¹ with G¹ to G⁵ that bond to the parent molecular moiety through a nitrogen atom.

Example 14 Preparation of (N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine) (Compound 195)

Preparation of 2-(3-bromo-1, 2,4-triazol-1-yl)pyrazine (JW-7c)

K₂CO₃ (19.1 g, 138.4 mmol), 3-bromo-4H-1,2,4-triazole (17.06 g, 115.3 mmol) and 2-chloropyrazine (13.2 g, 115.3 mmol) were mixed in NMP (100 mL) and the reaction was heated at 120° C. for 6 hrs. LCMS showed that the reaction was almost completed. The solid was filtered off when the reaction was still hot and the filtrate was left standing overnight. A solid precipitated out during this course and the solid was filtered and washed with cold diethyl ether to afford 13.4 g (46%) of desired product JW-7c. ¹H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.15 (d, J=1.2 Hz, 1H), 8.81 (t, J=3.9 Hz, 1H), 8.66 (dd, J=2.5, 1.4 Hz, 1H) ppm. ESI-MS m/z calc. 224.96501. found 226.25; (M+1)+; Retention time: 0.66 minutes.

Preparation of N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine (Compound 195)

2-(3-Bromo-1,2,4-triazol-1-yl)pyrazine JW-7c (120 mg, 0.53 mmol), sodium 2-methylpropan-2-olate(98 mg, 1.02 mmol), chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (31 mg, 0.29 mmol) and 3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline JW-1b (131 mg) were mixed in 2-methylpropan-2-ol (1.8 mL) and the reaction was degassed with nitrogen for 30 seconds then heated at 60° C. for 2 hours. The reaction was cooled to R.T. and water (1 mL) was added. The reaction was extracted with DCM and organic layer was dried and concentrated in vacuo. The crude was purified on silica gel (12 gram column, using 1-4% DCM: MeOH) to afford 148 mg (58%) of desired product cmpd 195. ¹H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.20 (s, 1H), 9.05 (d, J=1.4 Hz, 1H), 8.66 (d, J=2.5 Hz, 1H), 8.58 (dd, J=2.6, 1.4 Hz, 1H), 7.16 (s, 1H), 6.93 (s, 1H), 6.34 (s, 1H), 4.57 (t, J=6.5 Hz, 2H), 4.52-4.41 (m, 2H), 3.46 (dt, J=11.1, 5.6 Hz, 1H), 3.16 (dd, J=5.1, 3.7 Hz, 4H), 2.47-2.38 (m, 4H), 2.26 (d, J=8.1 Hz, 3H) ppm. ESI-MS m/z calc. 392.2073. found 393.48; (M+1)+; Retention time: 0.59 minutes.

Example 15 Preparation of N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine (Compound 20)

Preparation of 1-cyclopropyl-4-(3-methyl-5-nitro-phenyl)piperazine (JW-8a)

3-Bromo-5-nitro-toluene, (7.78 g, 36.0 mmol) and 1-cyclopropylpiperazine (5.0 g, 39.6 mmol) were dissolved in 100 mL of dry t-BuOH and purged with N2 for 10 minutes. During the purge added t-BuXphos Palladacycle (620 mg, 0.90 mmol) followed by sodium t-butoxide, (5.20 g, 54.0 mmol) and reaction was allowed to stir at 30° C. under N2 for two hours. Solvent was removed under reduced pressure and the residue partitioned between EtOAc and water, then the organic phase washed with brine, dried (Na₂SO₄) and solvent removed under reduced pressure. The crude material was Isco purified on SiO2 with DCM changing to isocratic 10%/EtOAc/DCM as eluent to afford 6.75 g (64%) of JW-8a as a dark yellow, waxy solid. ¹H NMR (400 MHz, Acetone-d6) δ 7.51 (t, J=2.1 Hz, 1H), 7.43 (d, J=0.6 Hz, 1H), 7.21 (s, 1H), 3.35-3.18 (m, 4H), 2.83-2.67 (m, 4H), 2.40 (s, 3H), 1.75-1.59 (m, 1H), 0.57-0.41 (m, 2H), 0.38 (dt, J=3.8, 2.5 Hz, 2H) ppm. ESI-MS m/z calc. 261.14774. found 262.0; (M+1)+; Retention time: 0.58 minutes.

Preparation of 3-(4-cyclopropylpiperazin-1-yl)-5-methyl-aniline (JW-8b)

1-cyclopropyl-4-(3-methyl-5-nitro-phenyl)piperazine JW-8a (6.75 g, 25.4 mmol) was dissolved in 200 mL of MeOH and placed under a CO₂ atmosphere before adding 10% Pd/C Degussa type 50% water (700 mg; 0.65 mmol). Reaction placed under 50 psi H₂ for 24 hours. Reaction was pulled through a pad of diatomaceous earth and washed the cake with more MeOH. Solvent was removed under reduced pressure to afford 6.1 g (90%) of JW-8b as a tan, partially solidified oil. ¹H NMR (400 MHz, Acetone-d6) δ 6.07 (t, J=2.0 Hz, 1H), 6.05 (d, J=0.5 Hz, 1H), 6.01-5.93 (m, 1H), 3.02 (dd, J=5.9, 4.2 Hz, 4H), 2.74-2.60 (m, 4H), 2.12 (d, J=0.4 Hz, 3H), 1.70-1.54 (m, 1H), 0.50-0.37 (m, 2H), 0.38-0.26 (m, 2H) ppm. ESI-MS m/z calc. 231.17355. found 232.0; (M+1)+; Retention time: 0.27 minutes.

Preparation of N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine (Compound 20)

3-(4-Cyclopropylpiperazin-1-yl)-5-methyl-aniline JW-8b (122.7 mg, 0.53 mmol), sodium t-butoxide (154.3 mg, 1.606 mmol), t-BuXPhos Palladacycle (15 mg, 0.02 mmol) and 2-(3-bromo-1,2,4-triazol-1-yl)pyrazine JW-7c (119 mg, 0.53 mmol) were mixed in t-BuOH (1.5 mL) and the reaction was degassed with nitrogen for 20 seconds, then heated at 60 degrees for 2 hours. The reaction was cooled to R.T. and water was added. The reaction was extracted with DCM and organic layer dried and concentrated in vacuo. The crude was purified on silica gel eluting with 1-4% DCM: MeOH to afford 91 mg (37%) of desired product cmpd 20. ¹H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.19 (s, 1H), 9.05 (d, J=1.2 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.58 (dd, J=2.6, 1.4 Hz, 1H), 7.15 (s, 1H), 6.92 (s, 1H), 6.33 (s, 1H), 3.16-3.03 (m, 4H), 2.79-2.66 (m, 4H), 2.24 (s, 3H), 1.75-1.56 (m, 1H), 0.52-0.41 (m, 2H), 0.37-0.30 (m, 2H) ppm. ESI-MS m/z calc. 376.2124. found 377.46; (M+1)+; Retention time: 0.61 minutes.

Using the general synthetic scheme outlined in Scheme D and the experimental procedures listed above in Examples 14 and 15, the following compounds were prepared:

Cmpd No. IUPAC Name 381 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyrimidin- 5-yl-1,2,4-triazol-3-amine 399 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyridazin-4-yl- 1,2,4-triazol-3-amine 275 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- pyridyl)-1,2,4-triazol-3-amine 104 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 224 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- pyridyl)-1,2,4-triazol-3-amine 68 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyrazin-2-yl- 1,2,4-triazol-3-amine 342 5-methyl-N1-[1-(oxetan-3-yl)-4-piperidyl]-N3-[1-(3-pyridyl)- 1,2,4-triazol-3-yl]benzene-1,3-diamine 249 N3-[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 329 1-(4,6-difluoro-2-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 174 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 176 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 288 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 271 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 401 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 420 N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 154 1-(6-fluoro-2-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 75 N-[3-[4-(3,3-difluorocyclobutyl)piperazin-1-yl]-5-methyl- phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 124 N-(3-ethyl-5-piperazin-1-yl-phenyl)-1-pyrazin-2-yl-1,2,4-triazol- 3-amine 368 tert-butyl 4-[3-ethyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]piperazine-1-carboxylate 470 N-[2,3-dimethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 471 N-[2-methoxy-3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 451 N-(2-fluoro-3-methyl-5-morpholino-phenyl)-1-(3-pyridyl)-1,2,4- triazol-3-amine 307 N-(2-fluoro-3-methyl-5-morpholino-phenyl)-1-(2-pyridyl)-1,2,4- triazol-3-amine 387 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 262 1-(5-chloro-3-pyridyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 217 1-(5-chloro-3-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 232 1-(2,6-difluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 111 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 254 1-(6-methoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 312 1-(2,6-dimethylpyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 418 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 204 1-(2-ethoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 30 1-(2-methoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 364 1-[6-(methoxymethyl)pyrimidin-4-yl]-N-[3-methyl-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 314 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 58 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 91 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 64 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylsulfanylpyrimidin-4-yl)-1,2,4-triazol-3-amine 132 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylsulfanylpyrimidin-4-yl)-1,2,4-triazol-3-amine 291 1-(5-fluoropyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 50 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(5- fluoropyrimidin-4-yl)-1,2,4-triazol-3-amine 495 1-[2-(azepan-1-yl)-4-pyridyl]-N-[3-methyl-5-(4-methylpiperazin- 1-yl)phenyl]-1,2,4-triazol-3-amine 138 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-(2-pyridyl)- 1,2,4-triazol-3-amine 297 N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-(3-pyridyl)- 1,2,4-triazol-3-amine 211 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 122 1-(2-fluoro-4-pyridyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]-5- methyl-phenyl]-1,2,4-triazol-3-amine 464 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 385 N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1-(4- pyridyl)-1,2,4-triazol-3-amine 226 1-(2-fluoro-4-pyridyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 96 N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 13 N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1-(4- pyridyl)-1,2,4-triazol-3-amine 48 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-pyrazin-2- yl-1,2,4-triazol-3-amine 300 1-[3-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]-1-piperidyl]ethanone 236 N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5-propyl-phenyl]-1-pyrazin- 2-yl-1,2,4-triazol-3-amine 511 N-[3-isopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 521 N-[3-methyl-5-[4-(oxetan-3-yl)-1-piperidyl]phenyl]-1-pyrazin-2- yl-1,2,4-triazol-3-amine 535 N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine 536 N-[3-isopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 550 N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine 549 N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-pyrimidin- 5-yl-1,2,4-triazol-3-amine 539 N-[3-cyclopropyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 544 N-[3-ethyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-pyrimidin-5- yl-1,2,4-triazol-3-amine 598 N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 811 N-[3-isopropoxy-2-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine 862 N-[3-isopropoxy-2-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine

Compounds of the invention may be prepared as generally outlined in Scheme E, where R², R⁴⁰ and X¹ are as described for Scheme A. The methods of Scheme E may also be applied to other variations of L¹ with G¹ to G² that bond to -L²-R⁶, -L²-R⁷, or optional G² substituent through a nitrogen atom in G¹ or G².

Example 16 Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 215)

Preparation of 2-[3-bromo-N-(2-hydroxyethyl)-5-methyl-anilino]ethanol (YL-4a)

A mixture of 3-bromo-5-methyl-aniline (1.86 g, 10 mmol), 2-chloroethanol (3.22 g, 40.00 mmol), KI (166 mg, 1.00 mmol) and CaCO₃ (2.00 g, 20.00 mmol) in water (6 mL) and EtOH (6 mL) was heated at 100° C. for 36 h, then at 120° C. for 20 h. The reaction mixture was cooled to RT, diluted with EtOAc, washed with H₂O, sat. NaCl and dried then evaporated under reduced pressure. The crude material was subjected to ISCO purification (40 g silica; 0% to 10% of MeOH in DCM) to give 2-[3-bromo-N-(2-hydroxyethyl)-5-methyl-anilino]ethanol YL-4a (1.4 g, 51%). ¹H NMR (300 MHz, CDCl₃) δ 6.71 (d, J=22.0 Hz, 2H), 6.47 (s, 1H), 3.87 (t, J=4.9 Hz, 4H), 3.61-3.53 (m, 4H), 3.41 (s, 2H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 273.04. found 274.31; (M+1)+; Retention time: 0.68 minutes.

Preparation of 2-[3-bromo-5-methyl-N-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate (YL-4b)

To 2-[3-bromo-N-(2-hydroxyethyl)-5-methyl-anilino]ethanol YL-4a (720 mg, 2.63 mmol) in EtOAc (15 mL) was added methanesulfonyl chloride (902 mg, 7.88 mmol) and Et₃N (930 mg, 9.19 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with EtOAc, washed with water, sat. NaHCO₃, sat. NaCl and dried then evaporated under reduced pressure. The crude material was subjected to ISCO purification (40 g silica; 10% to 100% of EtOAc in hex) to give 2-[3-bromo-5-methyl-N-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate YL-4b (950 mg, 84%). ¹H NMR (300 MHz, CDCl₃) δ 6.79 (s, 1H), 6.67 (d, J=1.8 Hz, 1H), 6.47 (s, 1H), 4.37 (t, J=5.8 Hz, 4H), 3.76 (t, J=5.8 Hz, 4H), 3.02 (s, 6H), 2.30 (s, 3H) ppm. ESI-MS m/z calc. 428.99. found 430.24; (M+1)+; Retention time: 0.85 minutes.

Preparation of 1-(3-bromo-5-methyl-phenyl)-4-(3-methyloxetan-3-yl)piperazine (YL-4c)

A mixture of 2-[3-bromo-5-methyl-N-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate YL-4b (220 mg, 0.51 mmol), 3-methyloxetan-3-amine (54 mg, 0.62 mmol) and K₂CO₃ (212 mg, 1.53 mmol) in dioxane (15 mL) was microwaved at 160° C. for 16 h. ISCO purification of the crude material (12 g silica; 10% to 50% to 100% of EtOAc in hex) gave 1-(3-bromo-5-methyl-phenyl)-4-(3-methyloxetan-3-yl)piperazine YL-4c (85 mg, 51%). ¹H NMR (300 MHz, CDCl₃) δ 6.86 (d, J=1.8 Hz, 1H), 6.83 (s, 1H), 6.65 (s, 1H), 4.64 (d, J=5.4 Hz, 2H), 4.29 (d, J=5.8 Hz, 2H), 3.29-3.13 (m, 4H), 2.61-2.44 (m, 4H), 2.35-2.22 (m, 3H), 1.42 (s, 3H) ppm. ESI-MS m/z calc. 324.08. found 325.39; (M+1)+; Retention time: 0.64 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (Compound 215)

1-(3-Bromo-5-methyl-phenyl)-4-(3-methyloxetan-3-yl)piperazine (440 mg, 1.35 mmol), 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (319 mg, 1.62 mmol) and sodium t-butoxide (325 mg, 3.38 mmol) were suspended in dioxane (20 mL) and purged with N2 for several minutes before addition of t-BuXPhos Palladacycle (88 mg, 0.14 mmol). The mixture was microwaved at 120° C. for 40 minutes. LC/MS showed desired product. The reaction was quenched with MeOH (2 mL) and diluted with DCM, then solvent was removed by evaporation under reduced pressure. The solids were triturated with water, then were collected and dissolved in 20% MeOH in DCM. After filtration through Florisil (10 g), the excess solvent was pumped down. The solids were triturated with EtOAC, ether and dried. The above product was dissolved in MeOH/DCM (1:9; 100 mL) 3 equivalents of MP-TMT (F15118/Biotage/0.64 mmol/g; 3 g) were added and rotated at 45-50° C. for 4 h. After filtration, the excess solvent was pumped down to afford 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine, cmpd 215 (1750 mg, 72%). ¹H NMR (300 MHz, CD₃OD) δ 8.60 (s, 1H), 7.33 (d, J=6.6 Hz, 2H), 7.15 (s, 1H), 6.79 (d, J=14.4 Hz, 2H), 6.37 (s, 1H), 4.63 (d, J=5.1 Hz, 2H), 4.26 (d, J=5.3 Hz, 2H), 3.24 (s, 4H), 2.53 (s, 4H), 2.28 (s, 3H), 1.40 (s, 3H) ppm. ESI-MS m/z calc. 440.21. found 441.45; (M+1)+; Retention time: 0.69 minutes.

Example 17 Preparation of N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 436)

Preparation of N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 436)

1-(3-bromo-5-methyl-phenyl)-4-(3-methyloxetan-3-yl)piperazine YL-4c (180 mg, 0.55 mmol), 1-phenyl-1,2,4-triazol-3-amine (106 mg, 0.66 mmol) and sodium t-butoxide (133 mg, 1.38 mmol) were suspended in dioxane (10 mL) and purged with N₂ for several minutes before addition of the t-BuXPhos Palladacycle (36 mg, 0.055 mmol). The mixture was microwaved at 120° C. for 40 minutes. LC/MS showed desired product. The reaction was quenched with MeOH (2 mL), then diluted with DCM and filtered (Florisil/5 g). The filtrate was evaporated in vacuo then subjected to ISCO purification (12 g silica; 10% to 50% to 100% of EtOAc in hex) to give N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine, cmpd 436 (153 mg, 65%). ¹H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.74-7.65 (m, 2H), 7.56-7.46 (m, 2H), 7.41-7.32 (m, 1H), 7.12 (d, J=1.9 Hz, 1H), 6.83 (s, 1H), 6.65 (s, 1H), 6.41 (s, 1H), 4.67 (d, J=5.5 Hz, 2H), 4.30 (d, J=5.8 Hz, 2H), 3.37-3.22 (m, 4H), 2.64-2.48 (m, 4H), 2.35 (s, 3H), 1.44 (s, 3H) ppm. ESI-MS m/z calc. 404.23. found 405.45; (M+1)+; Retention time: 0.66 minutes.

Using the general synthetic scheme outlined in Scheme E and the experimental procedures listed above in Examples 16 and 17, the following compounds were prepared:

Cmpd No. IUPAC Name 375 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 469 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 264 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 489 N-[3-ethyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 505 [3-acetoxy-2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]-2-methyl- propyl]acetate 534 [2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-3-hydroxy-2-methyl- propyl]acetate 215 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine

Compounds of the invention may be prepared as generally outlined in Scheme F, where R², R⁴⁰ and X¹ are as described for Scheme A. The methods of Scheme F may also be applied to other variations of G¹ to G⁵ that bond to the parent molecular moiety through a carbon atom.

Example 18 Preparation of N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 363)

Preparation of (3-(3-bromo-5-methyl-phenyl)oxetane) PC-1a

A microwave 20 ml vial was charged with (3-bromo-5-methyl-phenyl)boronic acid (2.34 g, 10.9 mmol), (1R,2R)-2-aminocyclohexan-1-ol hydrochloride (82 mg, 0.544 mmol), NiI₂ (170 mg, 0.544 mmol) and (bis(trimethylsilyl)amino)sodium (1.99 g, 10.9 mmol). The mixture was capped and then placed under a nitrogen atmosphere. iPrOH (8.5 mL) and 3-iodooxetane (1 g, 5.44 mmol) were added and the mixture microwaved for 30 min at 120° C. The mixture was filtered through Florisil with the aid of EtOAc and concentrated to dryness. Purification by column chromatography (80 g column; 25-100% EtOAc in hexane over 8 min) gave 3-(3-bromo-5-methyl-phenyl)oxetane PC-1a (420 mg, 34%) as a colorless oil. ¹H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 5.06 (dd, J=8.3, 6.1 Hz, 2H), 4.73 (t, J=6.3 Hz, 2H), 4.19-4.11 (m, 1H), 2.35 (s, 3H) ppm.

Preparation of (N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-phenyl-1,2,4-triazol-3-amine) (Compound 363)

A Schlenk tube was charged with 3-(3-bromo-5-methyl-phenyl)oxetane PC-1a (143 mg, 0.630 mmol), 1-phenyl-1,2,4-triazol-3-amine RG-1b (101 mg, 0.567 mmol), X-phos palladacycle (Strem 46-0268, 19 mg, 0.025 mmol) and sodium tert-butoxide (121 mg, 1.26 mmol) then dioxane (2 mL) and vacuum/nitrogen cycled two times. The tube was immersed in a bead bath set to 70° C. for 3 h at which point DCM and water were added. The layers were separated through a phase separator and the organics were concentrated to dryness. After purification by column chromatography (C18 AQ 40 g column; aq. TFA/MeCN) the pure fractions were passed through a SPE bicarbonate cartridge (Agilent Stratospheres 5 g/60 mL) and concentrated to dryness. Trituration with MeOH gave N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-phenyl-1,2,4-triazol-3-amine, cmpd 363 (60 mg, 31%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.08 (s, 1H), 7.85 (dd, J=8.6, 1.1 Hz, 2H), 7.56 (dd, J=10.7, 5.3 Hz, 3H), 7.40-7.29 (m, 2H), 6.71 (s, 1H), 4.95 (dd, J=8.4, 5.8 Hz, 2H), 4.62 (dd, J=6.7, 5.8 Hz, 2H), 4.23-4.11 (m, 1H), 2.28 (d, J=6.4 Hz, 3H) ppm. ESI-MS m/z calc. 306.1481. found 307.18; (M+1)⁺; Retention time: 0.77 minutes.

Using the general synthetic scheme outlined in Scheme F and the experimental procedures listed above in Example 18, the following compounds were prepared:

Cmpd No. IUPAC Name 229 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)azetidin-3-yl]phenyl]-1,2,4-triazol-3-amine 65 N-[3-methyl-5-[1-(oxetan-3-yl)azetidin-3-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 36 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)azetidin-3- yl]phenyl]-1,2,4-triazol-3-amine 301 1-(3,4-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)azetidin-3-yl]phenyl]-1,2,4-triazol-3-amine 313 1-(3,5-difluorophenyl)-N-[3-(oxetan-3-yl)-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 147 1-(3-fluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine 404 N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-(2-pyridyl)-1,2,4- triazol-3-amine 270 N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-(3-pyridyl)-1,2,4- triazol-3-amine 131 1-(3,5-difluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine 409 1-(4-fluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine 447 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine

Compounds of the invention may be prepared as generally outlined in Scheme G, where R², R³, R⁴, R¹⁰⁰, and X¹ are as described for Scheme A. The methods of Scheme G may also be applied to other variations of L¹ with G¹ to G⁵ that bond to the parent molecular moiety through a nitrogen atom.

Example 19 Preparation of N-(3-cyclopropyl-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1-(3,5-difluorophenyl)-1H-1,2,4-triazol-3-amine (Compound 389)

Preparation of 1-bromo-3-cyclopropyl-5-nitrobenzene(HG-2a)

A dioxane (313 mL) mixture of 1,3-dibromo-5-nitro-benzene (8.8 g, 31.3 mmol), cyclopropylboronic acid (2.96 g, 34.5 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (2.292 g, 3.13 mmol) and K₃PO₄ (33.24 g, 156.6 mmol) was stirred at 90° C. for 4 h. LCMS indicated a new peak. To the reaction mixture was added EA and brine, the organic phase was dried over MgSO₄, filtered, concentrated down and purified on an Isco 220 g column with heptanes and EA, the product and side product were eluted with 3% EA and 97% heptanes. NMR indicated the desired product and side product in a 2.5 to 1 ratio. The side product was carried on and removed in the next step. (3.52 g, 10.18 mmol, 33%)¹H NMR (300 MHz, CDCl₃) δ 8.15 (t, J=1.9 Hz, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.54 (t, J=1.6 Hz, 1H), 2.07-1.89 (m, 2H), 1.18-1.10 (m, 2H), 0.85-0.79 (m, 2H) ppm. Note: NMR spectrum is a mixture of 1-bromo-3-cyclopropyl-5-nitrobenzene and 1,3-dicyclopropyl-5-nitro-benzene.

Preparation of 1-(3-cyclopropyl-5-nitrophenyl)-4-(oxetan-3-yl)piperazine (HG-2b)

To a t-BuOH (57.68 mL) solution of 1-bromo-3-cyclopropyl-5-nitro-benzene HG-2a (5 g, 14.5 mmol) and 1-(oxetan-3-yl)piperazine (2.467 g, 17.4 mmol) was added t-BuXPhos Palladacycle (471 mg, 0.723 mmol) and t-BuOK (4.868 g, 43.4 mmol) and the reaction mixture was stirred at 80° C. for 1 h. LCMS indicated the major peak was desired product. Work up: To the reaction mixture was added EA and brine, organic phase was dried over MgSO₄, filtered, concentrate d to dryness and purified by Isco 80 g silica gel column eluting with heptanes and EA. The product was eluted with 100% EA to give 1-(3-cyclopropyl-5-nitrophenyl)-4-(oxetan-3-yl)piperazine HG-2b (2.4 g, 55%)¹H NMR (400 MHz, CDCl₃) δ 7.52 (t, J=2.2 Hz, 1H), 7.36 (t, J=1.6 Hz, 1H), 6.98 (dd, J=11.3, 9.5 Hz, 1H), 4.70 (dt, J=12.3, 6.4 Hz, 4H), 3.58 (p, J=6.4 Hz, 1H), 3.38-3.27 (m, 4H), 2.60-2.45 (m, 4H), 2.04-1.88 (m, 1H), 1.11-0.97 (m, 2H), 0.80-0.71 (m, 2H) ppm. ESI-MS m/z calc. 303.1583. found 304.16; (M+1)⁺; Retention time: 0.58 minutes.

Preparation of 3-cyclopropyl-5-(4-(oxetan-3-yl)piperazin-1-yl)aniline(HG-2c)

To a THF (23 mL) and EtOH (23 mL) solution of 1-(3-cyclopropyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine HG-2b (2.3 g, 7.582 mmol) was added NH₄Cl (37.91 mL of 2 M, 75.82 mmol) and Fe (1.27 g, 22.8 mmol) and the reaction mixture was refluxed for 1 h. LCMS indicated the reaction was completed. Work up: The reaction mixture was cooled to RT and filtered through celite. To the filtrate was added EA and brine, the organic phase was dried over MgSO₄, filtered, and concentrated to dryness. The crude product was purified by Isco 150 g Gold amine column eluting with heptanes and EA. The product was eluted with 50% heptanes and 50% EA to give 3-cyclopropyl-5-(4-(oxetan-3-yl)piperazin-1-yl)aniline HG-2c (1.6 g, 77%). ¹H NMR (400 MHz, CDCl₃) δ 6.22-6.13 (m, 1H), 6.08 (t, J=2.1 Hz, 1H), 5.96 (t, J=1.6 Hz, 1H), 4.78-4.61 (m, 4H), 3.56 (s, 2H), 3.27-3.12 (m, 4H), 2.50 (dd, J=15.6, 10.6 Hz, 4H), 1.79 (tt, J=8.4, 5.1 Hz, 1H), 0.95-0.82 (m, 2H), 0.74-0.58 (m, 2H) ppm. ESI-MS m/z calc. 273.1841. found 274.18; (M+1)⁺; Retention time: 0.2 minutes.

Preparation of N-(3-cyclopropyl-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1-(3,5-difluorophenyl)-1H-1,2,4-triazol-3-amine (Compound 389)

To a t-BuOH (1.6 mL) solution of 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole (104 mg, 0.4 mmol) and 3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline HG-2c (115 mg, 0.42 mmol) was added t-BuXPhos Palladacycle (13 mg, 0.02 mmol) and t-BuOK (135 mg, 1.2 mmol) and the reaction mixture was stirred at 85° C. for 1 h. LCMS indicated the major peak was desired product. Work up: To the reaction mixture was added EA and brine, the organic phase was concentrated down and purified by Isco Gold 150 g C18 column eluting with H2O/CH3CN/TFA. The product fractions were extracted with EA, the organic phase was dried over MgSO₄, filtered and concentrated down to afford N-(3-cyclopropyl-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1-(3,5-difluorophenyl)-1H-1,2,4-triazol-3-amine, cmpd 389 (69 mg, 37% yield). ¹H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.24 (dd, J=7.7, 2.0 Hz, 2H), 7.07 (t, J=2.0 Hz, 1H), 6.85-6.76 (m, 1H), 6.71 (s, 1H), 6.62 (s, 1H), 6.36 (s, 1H), 4.71 (p, J=6.3 Hz, 4H), 3.64-3.53 (m, 1H), 3.37-3.25 (m, 4H), 2.58-2.48 (m, 4H), 1.90 (ddd, J=13.4, 8.4, 5.0 Hz, 1H), 1.01-0.89 (m, 2H), 0.81-0.69 (m, 2H) ppm. ESI-MS m/z calc. 452.21362. found 453.28; (M+1)⁺; Retention time: 0.63 minutes.

Using the general synthetic scheme outlined in Scheme G and the experimental procedures listed above in Example 19, the following compounds were prepared:

Cmpd No. IUPAC Name 359 1-(3,5-difluorophenyl)-N-[3-isopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 222 2-cyclopropyl-6-morpholino-N-(1-phenyl-1,2,4-triazol-3- yl)pyridin-4-amine 405 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 305 N-(3-cyclopropyl-5-morpholino-phenyl)-1-phenyl-1,2,4- triazol-3-amine 339 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(5- fluoro-3-pyridyl)-1,2,4-triazol-3-amine 55 1-(3-chlorophenyl)-N-[3-cyclopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 494 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- fluoro-5-(3-methoxyazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 134 1-(5-chloro-3-pyridyl)-N-[3-cyclopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 184 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 47 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 32 1-(3-chloro-5-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 220 1-(3-chloro-5-fluoro-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 424 1-(3-fluoro-5-methyl-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 400 1-(3-chloro-5-fluoro-phenyl)-N-[3-cyclopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 73 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluoro-5-methyl-phenyl)-1,2,4-triazol-3-amine 388 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluoro-5-methoxy-phenyl)-1,2,4-triazol-3-amine 205 1-(3-fluoro-5-isopropoxy-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 462 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 285 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluoro-5-isopropoxy-phenyl)-1,2,4-triazol-3-amine 121 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]- 1-(2,6-difluoro-4-pyridyl)-1,2,4-triazol-3-amine 302 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 377 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 129 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]- 1-(2,6-dimethylpyrimidin-4-yl)-1,2,4-triazol-3-amine 454 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 286 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- ethoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 277 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 353 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[6- (methoxymethyl)pyrimidin-4-yl]-1,2,4-triazol-3-amine 225 N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluorophenyl)-1,2,4-triazol-3-amine 378 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(1- piperidyl)pyridin-4-amine 170 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- pyrrolidin-1-yl-pyridin-4-amine 327 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-(1- piperidyl)pyridin-4-amine 88 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 202 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methyl-1-piperidyl)pyridin-4-amine 244 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methyl-1-piperidyl)pyridin-4-amine 22 2-cyclopropyl-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]-6- (4-methyl-1-piperidyl)pyridin-4-amine 354 2-cyclopropyl-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 498 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 492 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3S)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 332 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3S)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 460 2-cyclopropyl-6-[(3S)-3-fluoropyrrolidin-1-yl]-N-(1-phenyl- 1,2,4-triazol-3-yl)pyridin-4-amine 44 2-cyclopropyl-6-(4-methyl-1-piperidyl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-4-amine 245 2-cyclopropyl-N-[1-(3,5-dimethoxyphenyl)-1,2,4-triazol-3-yl]-6- [(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 210 2-cyclopropyl-N-[1-(3,5-dimethoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 296 2-cyclopropyl-6-[(3R)-3-fluoropyrrolidin-1-yl]-N-(1-phenyl- 1,2,4-triazol-3-yl)pyridin-4-amine 9 2-cyclopropyl-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-N-(1- phenyl-1,2,4-triazol-3-yl)pyridin-4-amine 105 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine

Compounds of the invention may be prepared as generally outlined in Scheme H, where R², R³, R¹⁰⁰, and X¹ are as described for Scheme A. The methods of Scheme H may also be applied to other variations of L¹ with G¹ to G⁵ that bond to the parent molecular moiety through a nitrogen atom.

Example 20 Preparation of (1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1, 2,4-triazol-3-amine) (Compound 320)

Preparation of 3-fluoro-5-(3-nitro-1,2,4-triazol-1-yl)pyridine (JW-8c)

3-nitro-4H-1,2,4-triazole (JW-8b, 4.8 g, 42.1 mmol), (5-fluoro-3-pyridyl)boronic acid (5.93 g, 42.1 mmol), diacetoxycopper (JW-8a, 11.5 g, 63.1 mmol) and pyridine (6.66 g, 6.8 mL, 84.2 mmol) were mixed in DCM (200 mL) and the reaction was stirred at room temperature for 7 days. The solvent was evaporated and the material was re-dissolved in MeOH and DCM, then adsorbed onto 15 grams of silica gel. The material was dry-loaded and purified on silica gel (eluting with 10-70% EtoAc:Hexanes) to afford 1.2 g desired product JW-8c. ¹H NMR (400 MHz, DMSO-d6) δ 9.68 (d, J=3.3 Hz, 1H), 9.08 (dd, J=1.2, 0.5 Hz, 1H), 8.93-8.76 (m, 1H), 8.54-8.39 (m, 1H) ppm. ESI-MS m/z calc. 209.0349. found 210.41; (M+1)+; Retention time: 0.7 minutes.

Preparation of 1-(5-fluoro-3-pyridyl)-1,2,4-triazol-3-amine (JW-8d)

3-fluoro-5-(3-nitro-1,2,4-triazol-1-yl)pyridine (JW-5c, 170 mg, 0.82 mM) was dissolved into 10 mL of MeOH and placed under an atmosphere of CO₂. 85 mg of 10% Pd/C Degussa type 50% water catalyst was added into the reaction. The reaction was stirred at room temperature under a hydrogen atmosphere with an attached hydrogen-filled balloon overnight. The catalyst was removed by filtration and the filtrate was concentrated to afford 144 mg of desired product as a white solid (JW-8d) in 89% yield. ¹H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.88 (s, 1H), 8.45 (d, J=2.5 Hz, 1H), 8.06 (dt, J=10.2, 2.3 Hz, 1H) ppm. ESI-MS m/z calc. 179.06073. found 180.0; (M+1)+; Retention time: 0.51 minutes.

Preparation of 1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1,2,4-triazol-3-amine (Compound 320)

1-(3-bromo-5-methyl-phenyl)pyrrolidine (JW-5e, 80 mg, 0.33 mmol), 1-(5-fluoro-3-pyridyl)-1,2,4-triazol-3-amine (JW-8d, 60 mg, 0.33 mmol), sodium 2-methylpropan-2-olate (32 mg, 0.33 mmol) and t-BuXPhos Palladacycle (24 mg, 0.03 mmol) were dissolved in dioxane (2 mL) and the reaction was degassed with nitrogen for 10 seconds. The reaction was capped in a microwave tube and heated at 128 degrees in a microwave for 20 minutes. The reaction was quenched with 1 ml MeOH. The reaction was diluted with water and extracted with DCM. The organic phase was concentrated and the crude sample was purified on reverse phase. The fraction was free based with aq. NaHCO₃ and extracted with DCM. The organic layer was dried and concentrated. This material was dissolved in DCM and treated with HCl in ether to obtain 76 mg of white solid as the HCl salt of desired product cmpd 320 in 58% yield. ¹H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.30-9.24 (m, 1H), 9.11 (s, 1H), 8.45 (d, J=10.5 Hz, 1H), 7.76 (s, 1H), 7.10 (s, 1H), 6.64 (d, J=72.9 Hz, 1H), 3.52 (s, 3H), 2.46 (s, 1H), 2.30 (s, 2H), 2.09 (d, J=13.7 Hz, 4H) ppm. ESI-MS m/z calc. 338.16553. found 339.47; (M+1)+; Retention time: 0.71 minutes.

Using the general synthetic scheme outlined in Scheme H and the experimental procedures listed above in Example 20, the following compounds were prepared:

Cmpd No. IUPAC Name 403 1-(2-fluoro-4-pyridyl)-N-(3-methyl-5-morpholino-phenyl)-1,2,4- triazol-3-amine 155 4-[3-(3-methyl-5-morpholino-anilino)-1,2,4-triazol-1-yl]pyridin- 2-ol 427 1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-morpholino-phenyl)-1,2,4- triazol-3-amine 320 1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 371 N-(3-fluoro-5-morpholino-phenyl)-1-(5-fluoro-3-pyridyl)-1,2,4- triazol-3-amine 84 N-(3-methyl-5-morpholino-phenyl)-1-(4-pyridyl)-1,2,4-triazol-3- amine 42 1-(2-chloro-4-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 488 1-(6-chloro-2-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 503 4-methyl-6-(3-morpholinoazetidin-1-yl)-N-[1-(2-pyridyl)-1,2,4- triazol-3-yl]pyridin-2-amine 504 N-[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 507 N-[3-[4-(oxetan-3-yl)-1-piperidyl]-5-(trifluoromethyl)phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine 513 N-[3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 514 N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5-(trifluoromethyl)phenyl]- 1-pyrazin-2-yl-1,2,4-triazol-3-amine 529 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- piperazin-1-yl-pyridin-2-amine 532 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(2- pyridyl)-1,2,4-triazol-3-yl]pyridin-2-amine 533 tert-butyl 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-4-methyl-2-pyridyl]piperazine-1-carboxylate 684 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(3-pyridyl)-1,2,4-triazol- 3-yl]-4-(trifluoromethyl)pyridin-2-amine 763 3-morpholino-5-[[1-(3-pyridyl)-1,2,4-triazol-3- yl]amino]benzonitrile 666 3-morpholino-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]benzonitrile 842 3-[4-(oxetan-3-yl)piperazin-1-yl]-5-[[1-(3-pyridyl)-1,2,4-triazol- 3-yl]amino]benzonitrile

Compounds of the invention may be prepared as generally outlined in Scheme I, where LG₁ and LG₂ are leaving groups such as Br or Cl, R², R³, and R⁴⁰ are as described for Scheme A, and -L¹-R¹ is bonded to the parent molecular moiety through a nitrogen or carbon atom.

Example 20A Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine (Compound 485)

Preparation of 1-(3,5-difluorophenyl)-3-nitro-1H-1,2,4-triazole (RG-9a)

3-Nitro-1H-1,2,4-triazole (5.10 g, 44.71 mmol), diacetoxycopper (12.18 g, 67.06 mmol), (3,5-difluorophenyl)boronic acid (10.59 g, 67.06 mmol), 4A sieves (717.3 mg, 44.71 mmol) were mixed in DCE (200 mL) and pyridine (7.07 g, 7.23 mL, 89.42 mmol) was added. The reaction was stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the crude material was purified on silica gel (10-60% Hex: EtOAc) to afford 1-(3,5-difluorophenyl)-3-nitro-1H-1,2,4-triazole RG-9a (5.2 g, 20.2 mmol, 45%) 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.89-7.71 (m, 2H), 7.53 (tt, J=9.3, 2.3 Hz, 1H) ppm. ESI-MS m/z calc. 226.03023. found 227.03; (M+1)+; 227.03 (M−1)+; Retention time: 2.72 minutes.

Preparation of 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (RG-9b)

1-(3,5-difluorophenyl)-3-nitro-1,2,4-triazole RG-9a (16.6 g, 73.4 mM) was dissolved/suspended in 250 mL of MeOH and placed under a CO2 atmosphere before adding 10% Pd/C Degussa type 50% H2O; (2.5 g, 0.03 mM). Reaction was placed under an atmosphere of H₂ (50 psi) for 2.0 hours with agitation, then suctioned filtered the reaction through a pad of diatomaceous earth and washed with MeOH. Important note: much of the product resides on the pad due to it's insolubility. Washed everything back into the Parr bottle and diluted with 250 ml 3:7 MeOH/THF with fresh catalyst and replaced under 50 psi H2 for another 1.0 hours. note: no appreciable amounts of H2 taken up upon retreatment—hydroxyl amine is still present. Material was pulled through a pad of diatomaceous earth and washed with 7:3 THF/MeOH, until only the carbon remained and the solvents were removed under reduced pressure. Crude material was stirred in THF for one hour at ambient temperature, and isolated a light gray powder after suction filtration and washing with Et2O—filtrates retained. Note: most of the colour remains in filtrates and the precipitate has minimal amounts of the hydroxyl amine. Precipitate (8 g) was suspended in 16 mL of TFE and 25 mL of THF and heated to reflux, stirred until cool and isolated precipitate via suction filtration. Filtrates from the previous trituration were evaporated to dryness in vacuo and re-suspended in 25 mL of THF, heated to reflux and likewise stirred until cool. The precipitate from this THF trituration was added to the TFE/THF filtrates retained from the 1st batch, boiled, cooled, and isolated via suction filtration and combined with the 1st material. Yielded 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine RG-9b (10 g, 45.9 mmol, 63%). 1H NMR (400 MHz, Acetone-d6) δ 8.73 (s, 1H), 7.63-7.34 (m, 2H), 6.95 (tt, J=9.1, 2.3 Hz, 1H), 5.30 (brd s, 2H) ppm. ESI-MS m/z calc. 196.05605. found 197.0; (M+1)+; Retention time: 0.66 minutes.

Preparation of N-(3-chloro-5-methyl-phenyl)-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (RG-9c)

1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine RG-9b (1.8 g, 9.176 mmol), 1-bromo-3-chloro-5-methyl-benzene (3.76 g, 18.30 mmol), sodium t-butoxide (1.9 g, 19.77 mmol) and t-BuXphos Palladacyle (365 mg, 0.495 mmol) were dissolved into dry t-BuOH (21 mL) and dry dioxane (7 mL) and purged with N2 for ˜10 minutes. Stirred mixture at 90° C. for 1 h. LC/MS showed no remaining starting material so poured the reaction mixture into 250 mls of water and filtered. Washed the filter cake with additional water, then with methanol. Dried the filter cake in the high vac at 50° C. overnight. Yielded N-(3-chloro-5-methyl-phenyl)-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine RG-9c (2.4 g, 7.260 mmol, 79%) 1H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.20 (s, 1H), 7.63 (dd, J=8.6, 2.2 Hz, 2H), 7.55 (t, J=1.8 Hz, 1H), 7.34 (s, 1H), 7.28 (m, 1H), 6.76 (s, 1H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 320.06403. found 321.07; (M+1)+; Retention time: 1.03 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine (Compound 485)

Sodium t-butoxide (230 mg, 2.393 mmol), N-(3-chloro-5-methyl-phenyl)-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine RG-9c (200 mg, 0.5833 mmol), 4-(azetidin-3-yl)morpholine (125 mg, 0.8791 mmol), and t-BuXphos palladacycle (21 mg, 0.031 mmol) was added to a one dram vial. Diluted the solids with t-BuOH (3 mL) and dioxane (1 mL). Added a stir bar, flushed the reaction with nitrogen for 5 minutes, and sealed the vials. Heated to 50° C. LCMS showed after 30 minutes, very little desired product. Continued to stir for 6 h. Little change. Added additional t-Bu Xphos palladacycle (21 mg, 0.031 mmol) from a different bottle of catalyst and heated for another 30 minutes. The reaction is now complete. Diluted with DCM (10 mls) and washed organics with 50% saturated sodium bicarbonate. Combined organics from a previous run to purify in one batch. Passed the organics through a phase separator and concentrated to dryness. Diluted with 2 mls of DMSO and purified on a 275 gram C-18 AQ reverse phase column with a TFA modifier(0-100% ACN in water). Pooled desired pure tubes and diluted with DCM (10 mls) and washed with 50% saturated sodium bicarbonate. Passed the organics through a phase separator containing a plug of florisil, and concentrated to dryness to yield the desired product 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 485 (174 mg, 0.396 mmol, 68%) 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.15 (s, 1H), 7.60 (d, J=6.3 Hz, 2H), 7.24 (t, J=9.2 Hz, 1H), 6.72 (d, J=14.7 Hz, 2H), 5.82 (s, 1H), 3.89 (t, J=7.2 Hz, 2H), 3.58 (m, 6H), 3.25 (m, 1H), 2.34 (m, 4H), 2.19 (s, 3H) ppm. ESI-MS m/z calc. 426.19797. found 427.25; (M+1)+; Retention time: 0.66 minutes.

Using the general synthetic scheme outlined in Scheme I and the experimental procedures listed above in Example 20A, the following compounds were prepared:

Cmpd No. IUPAC Name 2 1-(3,5-difluorophenyl)-N-[3-(3-methoxyazetidin-1-yl)-5-methyl- phenyl]-1,2,4-triazol-3-amine 293 1-(3,5-difluorophenyl)-N-[3-(3-methoxy-1-piperidyl)-5-methyl- phenyl]-1,2,4-triazol-3-amine 116 1-(3,5-difluorophenyl)-N-[3-[3-(methoxymethyl)azetidin-1-yl]-5- methyl-phenyl]-1,2,4-triazol-3-amine 279 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-7- azaspiro[3.5]nonan-7-yl)phenyl]-1,2,4-triazol-3-amine 11 N-[3-methyl-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 326 N-[3-(4-isopropylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 253 N-[3-[4-(2-methoxyethyl)piperazin-1-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 274 N-[3-(4-ethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl-1,2,4- triazol-3-amine 214 1-cyclopropyl-4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-one 6 3-methyl-1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]pyrrolidin-3-ol 369 N-[3-[(3aR,6aR)-1-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3- c]pyrrol-5-yl]-5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 423 N-[3-methyl-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 455 N-[3-[4-(2-fluorophenyl)piperazin-1-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 289 N-[3-methyl-5-(4-tetrahydropyran-4-ylpiperazin-1-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 461 2-methyl-1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]propan-2-ol 398 N-[3-methyl-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 465 N-[3-(2,5-dihydrofuran-3-yl)-5-morpholino-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 298 1-(3,5-difluorophenyl)-N-[3-(2,5-dihydrofuran-3-yl)-5- morpholino-phenyl]-1,2,4-triazol-3-amine 165 N-(3-morpholino-5-tetrahydrofuran-3-yl-phenyl)-1-phenyl-1,2,4- triazol-3-amine 456 1-(3,5-difluorophenyl)-N-(3-morpholino-5-tetrahydrofuran-3-yl- phenyl)-1,2,4-triazol-3-amine 89 N-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 7 N-[3-methyl-5-(6-oxa-2-azaspiro[3.3]heptan-2-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 148 N-[3-[4-(2-methoxyethyl)-1-piperidyl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 40 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]anilino]-1- piperidyl]ethanone 112 1-(3,5-difluorophenyl)-N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 485 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 506 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(oxetan-3-yl)azetidin-1- yl]phenyl]-1,2,4-triazol-3-amine 508 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-6- azaspiro[3.3]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 510 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrrolidin-1-ylazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine 518 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-3-isopropyl-azetidin-3-ol 519 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]propan-2-ol 520 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(3- methoxycyclobutyl)-5-methyl-benzene-1,3-diamine 527 1-(3,5-difluorophenyl)-N-[3-methyl-5-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)phenyl]-1,2,4-triazol-3-amine 528 N-[3-(3,3a,4,6,7,7a-hexahydro-2H-furo[3,2-c]pyridin-5-yl)-5- methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 197 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1,5-dimethyl- N1-(oxetan-3-yl)benzene-1,3-diamine 240 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (oxetan-3-yl)benzene-1,3-diamine 325 1-(3,5-difluorophenyl)-N-[3-[2-(methoxymethyl)morpholin-4- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 349 1-(3,5-difluorophenyl)-N-[3-methyl-5-(9-methyl-2-oxa-6,9- diazaspiro[3.5]nonan-6-yl)phenyl]-1,2,4-triazol-3-amine 551 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-3-methyl-azetidin-3-ol 561 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one 553 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-3-ethyl-azetidin-3-ol 161 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]pyrrolidin-2-one 8 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- tetrahydrofuran-3-yl-benzene-1,3-diamine 542 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]pyrrolidin-2-one 566 N-[3-(3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8- yl)-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 164 1-(3,5-difluorophenyl)-N-[3-(3-methoxypyrrolidin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 541 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-8- azaspiro[3.5]nonan-8-yl)phenyl]-1,2,4-triazol-3-amine 552 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (trifluoromethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 355 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]azetidin-3-ol 543 1-(3,5-difluorophenyl)-N-[3-methyl-5-(9-oxa-6- azaspiro[3.5]nonan-6-yl)phenyl]-1,2,4-triazol-3-amine 855 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(2- methoxyethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 683 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methyl-3-morpholino- azetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 602 1-(3,5-difluorophenyl)-N-[3-[3-(2,2-dimethylmorpholin-4- yl)azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 857 1-(3,5-difluorophenyl)-N-[3-[3-[(2R,6R)-2,6-dimethylmorpholin- 4-yl]azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 617 1-(3,5-difluorophenyl)-N-[3-[3-(4-fluoro-1-piperidyl)azetidin-1- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 731 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(4- methylpiperazin-1-yl)pyridin-2-amine 702 6-(4-tert-butylpiperazin-1-yl)-N-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-4-methyl-pyridin-2-amine 631 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-amine 744 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(4- piperidyl)pyridin-2-amine 707 6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-2-carbonitrile 774 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3,6-dihydro-2H- pyran-4-yl)-4-methyl-pyridin-2-amine 801 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[1- (oxetan-3-yl)-4-piperidyl]pyridin-2-amine 724 1-(3,5-difluorophenyl)-N-[3-(2,5-dioxa-8-azaspiro[3.5]nonan-8- yl)-5-methyl-phenyl]-1,2,4-triazol-3-amine 831 N-[3-[(8aS)-7,7-difluoro-1,3,4,6,8,8a-hexahydropyrrolo[1,2- a]pyrazin-2-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4- triazol-3-amine 634 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(1-piperidyl)azetidin-1- yl]phenyl]-1,2,4-triazol-3-amine 690 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]-morpholino-methanone 742 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 730 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(2S)-2- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 618 1-(3,5-difluorophenyl)-N-[3-[3-[(2R,6S)-2,6-dimethylmorpholin- 4-yl]azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 696 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(2R)-2- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 800 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(3S)-3- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 670 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(3R)-3- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 711 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-N,N-dimethyl-azetidine-3-carboxamide 773 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]-pyrrolidin-1-yl-methanone 817 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-N,N-diethyl-azetidine-3-carboxamide 824 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-N-(2-methoxyethyl)-N-methyl-azetidine-3-carboxamide 584 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-N-[(1S)-2-methoxy-1-methyl-ethyl]azetidine-3- carboxamide 722 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)phenyl]-1,2,4-triazol-3-amine 727 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)phenyl]-1,2,4-triazol-3-amine 694 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 692 1-(3,5-difluorophenyl)-N-[3-methyl-5-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)phenyl]-1,2,4-triazol-3-amine 746 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 661 1-(3,5-difluorophenyl)-N-[3-[3-(1,1-dioxo-1,4-thiazinan-4- yl)azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 717 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 586 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(4-oxa-7- azaspiro[2.5]octan-7-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 788 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 720 1-(3,4-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 866 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (morpholinomethyl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 652 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(5-oxa-2- azabicyclo[4.1.0]heptan-2-yl)azetidin-1-yl]phenyl]-1,2,4-triazol- 3-amine 852 2-[3-fluoro-5-[3-[3-(3-fluoroazetidin-1-yl)-5-methyl-anilino]- 1,2,4-triazol-1-yl]anilino]ethanol 766 N-[3-(3-fluoroazetidin-1-yl)-5-methyl-phenyl]-1-[3-fluoro-5-(2- methoxyethylamino)phenyl]-1,2,4-triazol-3-amine 791 2-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]amino]ethanol 816 1-(3,5-difluorophenyl)-N-[3-[3-(2-methoxyethylamino)azetidin- 1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 704 N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 828 5-methyl-N3-(1-methylpyrazol-3-yl)-N1-(1-phenyl-1,2,4-triazol- 3-yl)benzene-1,3-diamine 604 N1-(1-ethyl-1,2,4-triazol-3-yl)-5-methyl-N3-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 830 1-(3,5-difluorophenyl)-N-[3-isopropoxy-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 653 1-(3,5-difluorophenyl)-N-[3-isopropoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 797 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(3- morpholinocyclobutyl)benzene-1,3-diamine 799 N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(3- morpholinocyclobutyl)benzene-1,3-diamine 822 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3-amine 628 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3-amine 669 N3-(1-isopropylpyrazol-3-yl)-5-methyl-N1-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 802 N-[3-ethyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]-1- (4-fluorophenyl)-1,2,4-triazol-3-amine 649 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-(3- morpholinocyclobutyl)benzene-1,3-diamine 861 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-(3- morpholinocyclobutyl)benzene-1,3-diamine 792 N1-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-(3- morpholinocyclobutyl)benzene-1,3-diamine 826 N1-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-(3- morpholinocyclobutyl)benzene-1,3-diamine 643 5-methyl-N3-(1-phenyl-1,2,4-triazol-3-yl)-N1-thiazol-2-yl- benzene-1,3-diamine 588 5-methyl-N1-(5-methylthiazol-2-yl)-N3-(1-phenyl-1,2,4-triazol- 3-yl)benzene-1,3-diamine 676 5-methyl-N3-(1-methyl-1,2,4-triazol-3-yl)-N1-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 838 5-methyl-N1-oxazol-2-yl-N3-(1-phenyl-1,2,4-triazol-3- yl)benzene-1,3-diamine 790 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 743 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 810 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N1-tetrahydropyran-4-yl-benzene-1,3-diamine 765 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N1-tetrahydrofuran-3-yl-benzene-1,3-diamine 699 5-methyl-N3-(5-methyl-1H-pyrazol-3-yl)-N1-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 593 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2- morpholinoethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 850 1-(3,5-difluorophenyl)-N-[3-[4-(3-methoxypropyl)piperazin-1- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 771 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3,3,4-trimethylpiperazin- 1-yl)phenyl]-1,2,4-triazol-3-amine 738 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1,5-dimethyl- N1-(2-morpholinoethyl)benzene-1,3-diamine 814 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-8- azaspiro[4.5]decan-8-yl)phenyl]-1,2,4-triazol-3-amine 582 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-morpholino-methanone 858 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-(2- morpholinoethyl)benzene-1,3-diamine 589 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]-morpholino-methanone 747 1-(3,5-difluorophenyl)-N-[3-[4-[3- (dimethylamino)propyl]piperazin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 772 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(4-methylpiperazin-1- yl)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 809 1-(3,5-difluorophenyl)-N-[3-[4-[2- (dimethylamino)ethyl]piperazin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 745 N-[3-[4-(3,3-difluoroazetidin-1-yl)-1-piperidyl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 948 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-N,N-dimethyl-piperidin-4-amine 1054 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]piperidin-3-ol 1035 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-oxa-7- azaspiro[2.5]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 1026 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-piperazin-2-yl]ethanol 875 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]cyclopentanol 1049 5-methyl-N1-(5-methyloxazol-2-yl)-N3-(1-phenyl-1,2,4-triazol- 3-yl)benzene-1,3-diamine 1045 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (tetrahydrofuran-3-ylmethyl)-4-piperidyl]benzene-1,3-diamine 917 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(2- ethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine 951 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[(1- morpholinocyclopropyl)methyl]benzene-1,3-diamine 896 1-(3,5-difluorophenyl)-N-[3-[4-(3-methoxypropyl)-1,4-diazepan- 1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 911 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholino-1- piperidyl)phenyl]-1,2,4-triazol-3-amine 895 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[(2- morpholinocyclopentyl)methyl]benzene-1,3-diamine 1023 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-methylmorpholin-4- yl)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 1003 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[2-(2,5- dimethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine 968 N3-[(4-cyclopropylmorpholin-2-yl)methyl]-N1-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 905 1-cyclopentyl-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-2-one 1027 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-(pyrrolidin-1- ylmethyl)morpholin-4-yl]phenyl]-1,2,4-triazol-3-amine 1017 N-[3-[2-(diethylaminomethyl)morpholin-4-yl]-5-methyl-phenyl]- 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1047 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(1-methyl-3- piperidyl)methyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 945 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-pyrrolidin-1- ylpropyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 944 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-pyrrolidin-1- ylethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1025 1-(3,5-difluorophenyl)-N-[3-[4-(4-ethylpiperazin-1-yl)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 996 1-(3,5-difluorophenyl)-N-[3-(5-ethyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)-5-methyl-phenyl]-1,2,4-triazol- 3-amine 1020 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[(3- pyrrolidin-1-yloxetan-3-yl)methyl]benzene-1,3-diamine 897 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(1-ethyl-3- piperidyl)-5-methyl-benzene-1,3-diamine 976 1-(3,5-difluorophenyl)-N-[3-(4-ethoxy-1-piperidyl)-5-methyl- phenyl]-1,2,4-triazol-3-amine 925 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-methyl-4-(1-methyl-4- piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1038 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-pyrrolidin-1-yl-1- piperidyl)phenyl]-1,2,4-triazol-3-amine 1030 1-(3,5-difluorophenyl)-N-[3-[2-(2-methoxyethyl)morpholin-4- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 889 N-[3-(1,4-diazabicyclo[3.2.1]octan-4-yl)-5-methyl-phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 1019 1-(3,5-difluorophenyl)-N-[3-(4-isopropoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 1001 1-(3,5-difluorophenyl)-N-[3-[4-(4-methoxybutyl)piperazin-1-yl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 987 N-[3-[4-[2-(diethylamino)ethyl]piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1068 1-(3,5-difluorophenyl)-N-[3-[4-(4-methoxy-1-piperidyl)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1006 1-(3,5-difluorophenyl)-N-[3-(4-methoxy-1-piperidyl)-5-methyl- phenyl]-1,2,4-triazol-3-amine 927 1-(3,5-difluorophenyl)-N-[3-[2-(isopropoxymethyl)morpholin-4- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 973 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethyl)piperazin-1-yl]-5- methyl-phenyl]-1,2,4-triazol-3-amine 956 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(1-methyl-4- piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 949 1-(3,5-difluorophenyl)-N-[3-[4-(1,4-dioxan-2- ylmethyl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1018 1-(3,5-difluorophenyl)-N-[3-[2- [(dimethylamino)methyl]morpholin-4-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 871 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methyl-4-morpholino- pyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 903 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[(4- isobutylmorpholin-2-yl)methyl]-5-methyl-benzene-1,3-diamine 1070 N1-(1-cyclobutyl-4-piperidyl)-N3-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 931 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(1- methyl-2-morpholino-ethyl)benzene-1,3-diamine 928 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[2- (2-methylmorpholin-4-yl)ethyl]benzene-1,3-diamine 1064 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(1- tetrahydrofuran-3-yl-4-piperidyl)benzene-1,3-diamine 890 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-tetrahydrofuran-3- ylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 974 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(5-ethyl-2- methyl-morpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine 1013 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(1- tetrahydropyran-4-yl-4-piperidyl)benzene-1,3-diamine 872 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(3- ethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine 991 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-tetrahydropyran-4-yl-methanone 870 1-(3,5-difluorophenyl)-N-[2-fluoro-3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 984 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(morpholinomethyl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 1036 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]ethanol 1024 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-methyl-piperazin-1-yl]-2-methyl-propan-2-ol 912 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(2- morpholinocyclopentyl)benzene-1,3-diamine 1033 2-[2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]ethoxy]ethanol 879 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]piperidin-4-ol 1079 [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-fluoro-azetidin-3-yl]methanol 1078 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-3-(dimethylamino)propan-2-ol 990 3-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propan-1-ol 964 3-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propan-1-ol 881 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)azetidin-3-yl]benzene-1,3-diamine 985 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(2- morpholinobutyl)benzene-1,3-diamine 901 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-oxa-7- azaspiro[3.4]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 1005 1-(3,5-difluorophenyl)-N-[3-[4-(2-isopropoxyethyl)piperazin-1- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1067 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-1-(2-methoxyethyl)piperazin-2-one 878 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]cyclohexanol 953 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5-methyl- N1-tetrahydrofuran-3-yl-benzene-1,3-diamine 1062 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[(4- methylmorpholin-3-yl)methyl]benzene-1,3-diamine 958 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]morpholin-2-yl]ethanol 1016 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5-methyl- N1-(3-methyloxetan-3-yl)benzene-1,3-diamine 1021 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5-methyl- N1-tetrahydropyran-4-yl-benzene-1,3-diamine 988 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methylmorpholin-4- yl)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 877 3-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]propan-1-ol 986 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-3-pyrrolidin-1- ylpyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine 995 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propan-2-ol 1040 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]pyrrolidin-3-yl]pyrrolidin-3-ol 1011 1-(3,5-difluorophenyl)-N-[3-[4-(2-methoxyethyl)-3-methyl- piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 880 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (2-morpholinoethyl)pyrrolidin-3-yl]benzene-1,3-diamine 1082 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[2- (3-methylmorpholin-4-yl)ethyl]benzene-1,3-diamine 874 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]ethanol 1050 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)-3-piperidyl]-5-methyl-benzene-1,3-diamine 1012 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine 930 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)-4-piperidyl]-5-methyl-benzene-1,3-diamine 1010 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-4-pyrrolidin-1-yl-pyrrolidin-3-ol 1014 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydrofuran-3- yloxy-1-piperidyl)phenyl]-1,2,4-triazol-3-amine 983 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine 894 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)pyrrolidin-3-yl]-5-methyl-benzene-1,3-diamine 939 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(2- morpholinocyclohexyl)benzene-1,3-diamine 972 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-tetrahydrofuran-2- ylmorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 1063 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethyl)-3-methyl- piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 936 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(tetrahydrofuran-3- ylmethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 888 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-tetrahydrofuran-2- ylmorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 1077 [1-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]pyrrolidin-2-yl]methyl]pyrrolidin-2-yl]methanol 933 1-(3,5-difluorophenyl)-N-[3-[4-[2-(dimethylamino)ethoxy]-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 904 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]butan-1-ol 893 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[(4- ethylmorpholin-2-yl)methyl]-5-methyl-benzene-1,3-diamine 892 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(1-methyl-3- piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 950 1-(3,5-difluorophenyl)-N-[3-[4-(2-fluoroethoxy)-1-piperidyl]-5- methyl-phenyl]-1,2,4-triazol-3-amine 906 1-(3,5-difluorophenyl)-N-[3-(3,7-dioxa-10-azaspiro[5.6]dodecan- 10-yl)-5-methyl-phenyl]-1,2,4-triazol-3-amine 954 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-[(4-methylpiperazin-1- yl)methyl]morpholin-4-yl]phenyl]-1,2,4-triazol-3-amine 962 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethoxy)-1-piperidyl]-5- methyl-phenyl]-1,2,4-triazol-3-amine 1057 1-(3,5-difluorophenyl)-N-[3-methyl-5-(8-oxa-4- azabicyclo[4.2.0]octan-4-yl)phenyl]-1,2,4-triazol-3-amine 1031 1-[3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]methyl]azetidin-1-yl]ethanone 946 2-[3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]methyl]azetidin-1-yl]propane-1,3-diol 1087 N-[3-[2-(cyclopropylmethoxymethyl)morpholin-4-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 902 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-2-methyl-piperazin-1-yl]ethanol 960 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (morpholinomethyl)propyl]benzene-1,3-diamine 924 1-(3,5-difluorophenyl)-N-[3-methyl-5-(7-oxa-1- azaspiro[3.5]nonan-1-yl)phenyl]-1,2,4-triazol-3-amine 1060 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrrolidin-1- ylpyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 919 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-2- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine 1056 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-2-ethyl-piperazin-1-yl]propan-2-ol 981 N-[3-(3,4,4a,5,7,7a-hexahydro-2H-furo[3,4-b]pyridin-1-yl)-5- methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1074 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-pyrrolidin-1- ylethoxy)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 891 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (tetrahydrofuran-2-ylmethyl)-4-piperidyl]benzene-1,3-diamine 1083 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-tetrahydrofuran-3- ylpyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 975 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(4-methylpiperazin-1- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 957 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]butan-2-ol 915 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N1-(oxetan-3-yl)benzene-1,3-diamine 1043 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]piperazin-1-yl]ethanol 969 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-N1,5- dimethyl-N1-(oxetan-3-yl)benzene-1,3-diamine 1015 2-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]-methyl-amino]ethanol 900 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-3-ethoxy-propan-2-ol 941 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-2-methyl-piperazin-1-yl]-2-methyl-propan-2-ol 1073 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]morpholin-2-yl]methanol 873 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- fluoroethyl)-3-piperidyl]-5-methyl-benzene-1,3-diamine 885 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(1,4-dioxan-2-ylmethyl)piperazin-1-yl]phenyl]- 1,2,4-triazol-3-amine 935 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(2,2-difluoroethyl)piperazin-1-yl]phenyl]-1,2,4- triazol-3-amine 922 2-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazin-1-yl]ethanol 961 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]methanone 1044 1-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazin-1- yl]ethanone 959 2,2,2-trideuterio-1-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]ethanone 926 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-tetrahydropyran-3-yl-piperazin-1-yl)phenyl]- 1,2,4-triazol-3-amine 1042 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-tetrahydrofuran-3-yl-piperazin-1-yl)phenyl]-1,2,4- triazol-3-amine 994 N-[3-(4-cyclobutyl-2,2,3,3,5,5,6,6-octadeuterio-piperazin-1-yl)- 5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 947 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-ethyl-piperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 884 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-(3- pyrrolidin-1-yltetrahydropyran-4-yl)benzene-1,3-diamine 914 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(tetrahydrofuran-2- ylmethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1046 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[(1- tetrahydropyran-4-yl-4-piperidyl)methyl]benzene-1,3-diamine 920 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-methyl-4-morpholino- pyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1007 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N1-(2-morpholinocyclopentyl)benzene-1,3-diamine 1072 1-(3,5-difluorophenyl)-N-[2-fluoro-3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine 979 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 916 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriopiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 963 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(3- ethylmorpholin-4-yl)ethyl]-2-fluoro-5-methyl-benzene-1,3- diamine 943 N1-(1-cyclobutyl-4-piperidyl)-N3-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-2-fluoro-5-methyl-benzene-1,3-diamine 1086 N-[3-methyl-5-[4-[1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl]piperazin-1-yl]phenyl]-1-phenyl-1,2,4- triazol-3-amine 929 N-[3-[4-(1-deuterio-1-methyl-ethyl)piperazin-1-yl]-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine 932 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-(1,4-dioxan-2- ylmethyl)-5-methyl-benzene-1,3-diamine 934 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- anilino]-1-(2-methoxyethyl)pyrrolidin-2-one 937 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[[1- (methoxymethyl)cyclopropyl]methyl]-5-methyl-benzene-1,3- diamine 882 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[2-(2,6- dimethylmorpholin-4-yl)propyl]-5-methyl-benzene-1,3-diamine 970 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2,2- dimethyltetrahydropyran-4-yl)-5-methyl-benzene-1,3-diamine 992 N1-[1-(2,2-difluoroethyl)-4-piperidyl]-N3-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 938 1-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]methyl]-N,N-dimethyl-cyclopentanecarboxamide 899 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (3,3,3-trifluoro-2-morpholino-propyl)benzene-1,3-diamine 1008 N3-[2-(cyclobutoxy)ethyl]-N1-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 1051 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2- (methylsulfonylmethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1048 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2,6- dioxaspiro[4.5]decan-9-yl)-5-methyl-benzene-1,3-diamine 942 N3-(cyclopropylmethyl)-N1-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 918 N1-(2-cyclopropyltetrahydropyran-4-yl)-N3-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 1075 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-3-methyl-azetidin-1-yl]-2-methoxy-ethanone 1084 tert-butyl 3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-anilino]methyl]azetidine-1-carboxylate 1037 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methylsulfonylazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine 1059 N1-(1-cyclopropylethyl)-N3-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 993 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- anilino]-1-pyrrolidin-1-yl-ethanone 940 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[2- (1-oxo-1,4-thiazinan-4-yl)ethyl]benzene-1,3-diamine 1004 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3-[(3- methyl-4,5-dihydroisoxazol-5-yl)methyl]benzene-1,3-diamine 1076 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-3-methyl-azetidine-3-carbonitrile 1029 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[(1- methoxycyclobutyl)methyl]-5-methyl-benzene-1,3-diamine 921 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]acetonitrile 887 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- anilino]-N,N-dimethyl-cyclobutanecarboxamide 1065 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2- methoxycyclopentyl)-5-methyl-benzene-1,3-diamine 1032 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 876 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 883 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone 1041 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-(difluoromethyl)- 5-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]phenyl]piperazin-1-yl]methanone 1066 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 982 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 1039 N-[3-[4-(3-deuteriotetrahydrofuran-3-yl)piperazin-1-yl]-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 1091 5-deuterio-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-[3-(trifluoromethyl)phenyl]- 1,2,4-triazol-3-amine 1092 2-[1-[3-[[5-deuterio-1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]azetidin-3-yl]propan-2-ol 1095 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3,4-difluorophenyl)-1,2,4-triazol-3- amine 1096 cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-(difluoromethyl)- 5-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3- yl]amino]phenyl]piperazin-1-yl]methanone 1097 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1098 1-(3,4-difluorophenyl)-N-[3-methyl-5-[3-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1099 N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3,4-difluorophenyl)-1,2,4-triazol-3- amine 1109 N3-benzyl-N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2- fluoro-5-methyl-benzene-1,3-diamine 1112 [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2-fluoro- 5-methyl-phenyl]piperazin-1-yl]-tetrahydropyran-4-yl-methanone 1113 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[3-methyl-4-(1- methyl-4-piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1114 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(2- ethylmorpholin-4-yl)ethyl]-2-fluoro-5-methyl-benzene-1,3- diamine 1115 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N1-[1-(tetrahydrofuran-3-ylmethyl)-4-piperidyl]benzene-1,3- diamine 1116 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N1-[1-(tetrahydrofuran-2-ylmethyl)-4-piperidyl]benzene-1,3- diamine 1117 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[3-(4- methylpiperazin-1-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 1118 N3-[(4-cyclopropylmorpholin-2-yl)methyl]-N1-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl-benzene- 1,3-diamine 1119 N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N1-(1-methyl-2-morpholino-ethyl)benzene-1,3-diamine 1120 1-(3,5-difluorophenyl)-N-[2-fluoro-3-[2- (isopropoxymethyl)morpholin-4-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 1121 N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl- N3-[(1-morpholinocyclopropyl)methyl]benzene-1,3-diamine 1122 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(3- tetrahydrofuran-3-ylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1123 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]-2-methyl-piperazin-1-yl]-2-methyl- propan-2-ol.

Compounds of the invention may be prepared as generally outlined in Scheme J, where R², R³, R⁴⁰, and X¹ are as described for Scheme A. The group

represents an R¹ group, or protected derivative thereof, attached to the parent molecule by a carbon atom. The methods of Scheme J are useful for preparing compounds where L¹ is a bond and R¹ is bonded to the parent molecular moiety by a carbon atom in R¹, including those having a hydroxyl or halo at the point of attachment on R¹ (e.g., D or E in Scheme J). Functional groups present in R¹ (e.g., amine) may be subject to further manipulation such as the steps of deprotection, reductive amination, and/or acylation to arrive at further compounds of the invention.

Example 21 Preparation of 1-(3,5-difluorophenyl)-N-r[3-methyl-5-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1,2,4-triazol-3-amine (Compound 221)

Preparation of t-butyl 4-(3-methyl-5-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (YL-12a)

A mixture of 1-bromo-3-methyl-5-nitro-benzene; (3.18 g, 14.7 mM) and t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate, (5 g, 16.17 mM) in dry dioxane (80 mL) was purged with N₂ for several minutes. Na₂CO₃ (20 mL; 2M) and Pd(dppf)Cl₂.DCM (1.08 g, 1.47 mM) was added and the reaction was heated at 70° C. for 3 hours. Pumped down solvent and the residue was partitioned between EtOAc and water. Organic phase was washed with water, brine, dried (Na₂SO₄) and solvent was removed under reduced pressure. Crude product was purified on SiO₂ with DCM=>EtOAc 0-50% to give t-butyl 4-(3-methyl-5-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate, YL-12a (2.7 g, 46.7%)¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.92 (s, 1H), 7.49 (s, 1H), 6.16 (s, 1H), 4.11 (t, J=7.1 Hz, 3H), 3.66 (t, J=5.6 Hz, 2H), 2.54 (s, 2H), 2.46 (s, 3H), 1.50 (s, 9H) ppm. ESI-MS m/z calc. 318.16. found 320.0; (M+1)+; Retention time: 0.93 minutes.

Preparation of t-butyl 4-(3-amino-5-methyl-phenyl)piperidine-1-carboxylate (YL-12b)

To t-butyl 4-(3-methyl-5-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.25 g, 7.07 mM) in MeOH (100 mL) under N₂, was added Pd on C, wet, Degussa (500 mg) and the reaction mixture was shaken under H₂ (50 psi) for 2 h. After filtration, the solvent was removed under reduced pressure to give t-butyl 4-(3-amino-5-methyl-phenyl)piperidine-1-carboxylate YL-12b (1.93 g, 84.7%). ¹H NMR (400 MHz, CDCl₃) δ 6.43 (s, 1H), 6.37 (s, 1H), 6.34 (s, 1H), 4.22 (s, 2H), 3.58 (s, 2H), 2.76 (s, 2H), 2.58-2.39 (m, 1H), 2.24 (s, 3H), 1.77 (d, J=12.8 Hz, 2H), 1.67-1.50 (m, 2H), 1.48 (s, 9H) ppm. ESI-MS m/z calc. 290.20. found 291.0. (M+1)+; Retention time: 0.64 minutes.

Preparation of t-butyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperidine-1-carboxylate (YL-12c)

A mixture of 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole (407 mg, 1.56 mmol) and t-butyl 4-(3-amino-5-methyl-phenyl)piperidine-1-carboxylate (500 mg, 1.72 mmol) in 10 mL of dry t-BuOH was purged with N₂ for several minutes. t-BuXPhos Palladacycle (100 mg, 0.16 mM) and sodium t-butoxide (225 mg, 2.35 mM) were added and the reaction mixture was heated at 30° C. under N₂ for 1 h. Reaction was quenched with MeOH and the solvent was pumped down. The residue was partitioned between EtOAc and water. The organic phase was washed with water, brine and dried (Na₂SO₄). Pumped down solvent. Crude materials were suspended in Et₂O and heated to reflux and cooled to RT. The solid was isolated, washed with Et₂O, hexanes and dried to give t-butyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperidine-1-carboxylate YL-12c (476 mg, 52.5%). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 6.83-6.76 (m, 1H), 6.67 (s, 1H), 4.25 (d, J=12.2 Hz, 2H), 2.81 (t, J=11.9 Hz, 2H), 2.72-2.50 (m, 1H), 2.36 (s, 2H), 1.85 (d, J=12.9 Hz, 2H), 1.66 (ddd, J=21.1, 15.7, 11.5 Hz, 4H), 1.49 (s, 9H) ppm. ESI-MS m/z calc. 469.23. found 470.0; (M+1)+; Retention time: 1.01 minutes.

Preparation of 1-(3,5-difluorophenyl-[3-methyl-5-(4-piperidyl)phenyl]-1,2,4-triazol-3-amine (YL-12d)

To a solution of tert-butyl 4-[3-[[1-(3,5-difluoro phenyl)-1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperidine-1-carboxylate (476 m g, 1.1 mmol) in DCM (10 mL) was added TFA (2 mL). The resultant mixture was stirred under N₂ for 2 h. Pumped down solvent. The residue was partitioned between EtOAc and sat'd Na₂CO₃. The organic layer was washed with brine and dried with Na₂SO₄. Pumped down solvent. Crude product were then triturated with hexanes/DCM (3:1) to give 1-(3,5-difluorophenyl-[3-methyl-5-(4-piperidyl)phenyl]-1,2,4-triazol-3-amine YL-12d (300 mg, 60%). ¹H NMR (400 MHz, Acetone-d6) δ 8.92 (s, 1H), 8.37 (s, 1H), 7.63-7.53 (m, 2H), 7.45 (s, 1H), 7.41 (s, 1H), 7.00 (tt, J=9.1, 2.3 Hz, 1H), 6.65 (s, 1H), 3.11 (d, J=11.9 Hz, 2H), 2.78-2.63 (m, 8H), 2.57 (tt, J=11.9, 3.7 Hz, 1H), 2.32 (s, 3H), 1.82-1.73 (m, 2H), 1.63 (qd, J=12.4, 4.0 Hz, 2H) ppm. ESI-MS m/z calc. 369.18. found 370.0. (M+1)+; Retention time: 0.62 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-r[3-methyl-5-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1,2,4-triazol-3-amine (Compound 221)

To a solution of 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-piperidyl)phenyl]-1,2,4-triazol-3-amine (129 mg, 0.31 mmol), oxetan-3-one YL-12d (226 mg, 3.14 mmol) and acetic acid (107 μL, 1.89 mmol) in dichloromethane (5.5 mL) was added NaBH(OAc)₃ (400 mg, 1.89 mmol). The mixture was stirred for 4 h. Reaction was diluted with DCM and quenched with MeOH and sat. NaHCO₃ (3 mL). After separation, the organic layer was washed with water, sat NaCl and dried. Pumped down solvent. ISCO purifications (12 g silica; 0% to 5% to 10% of MeOH in DCM) gave 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1,2,4-triazol-3-amine, cmpd 221 (123 mg, 87%)¹H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J=8.7, 2.2 Hz, 2H), 7.35 (s, 1H), 7.30-7.18 (m, 2H), 6.59 (s, 1H), 4.55 (t, J=6.5 Hz, 2H), 4.45 (t, J=6.1 Hz, 2H), 3.48-3.35 (m, 1H), 2.79 (d, J=11.1 Hz, 2H), 2.47-2.34 (m, 1H), 2.27 (s, 3H), 1.93-1.55 (m, 6H) ppm. ESI-MS m/z calc. 425.20. found 426.46; (M+1)+; Retention time: 0.67 minutes.

Using the general synthetic scheme outlined in Scheme J and the experimental procedures in Example 21 the following compounds were prepared:

Cmpd No. IUPAC Name 61 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3,6- dihydro-2H-pyridin-4-yl]phenyl]-1,2,4-triazol-3-amine 315 N-[3,5-bis(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 250 N-[3,5-di(tetrahydropyran-4-yl)phenyl]-1-(3-pyridyl)-1,2,4- triazol-3-amine 10 N-[3,5-di(tetrahydropyran-4-yl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 234 N-[3,5-bis(2,5-dihydrofuran-3-yl)phenyl]-1-phenyl-1,2,4-triazol- 3-amine 71 N-[3-methyl-5-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 221 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-4- piperidyl]phenyl]-1,2,4-triazol-3-amine 294 N-[3-methyl-5-[1-(3-methyloxetan-3-yl)-4-piperidyl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 51 N-[3-[1-[3-(benzenesulfonylmethyl)oxetan-3-yl]-4-piperidyl]-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 483 N-[3-methyl-5-[1-[(3-methyloxetan-3-yl)methyl]-4- piperidyl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 39 N-(3-methyl-5-pyrrolidin-3-yl-phenyl)-1-phenyl-1,2,4-triazol-3- amine 443 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]pyrrolidin-1-yl]ethanone 273 N-[3-[1-(2,2-difluoroethyl)pyrrolidin-3-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 452 N-(3-fluoro-5-pyrrolidin-3-yl-phenyl)-1-phenyl-1,2,4-triazol-3- amine 308 N-[3-methyl-5-(4-piperidyl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 108 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-piperidyl)phenyl]- 1,2,4-triazol-3-amine 333 N-[3-methyl-5-(1-methyl-4-piperidyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 151 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-methyl-4- piperidyl)phenyl]-1,2,4-triazol-3-amine 316 N-[3-methyl-5-(3-piperidyl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 429 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-piperidyl)phenyl]- 1,2,4-triazol-3-amine 60 N-[3-methyl-5-(1-methyl-3-piperidyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 328 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-methyl-3- piperidyl)phenyl]-1,2,4-triazol-3-amine 117 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]-1- piperidyl]ethanone 266 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]ethanone 194 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]-1- piperidyl]ethanone 90 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]ethanone 340 N-[3-(1-cyclopropyl-3-piperidyl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 120 N-[3-(1-cyclopropyl-4-piperidyl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 466 N-[3-(1-cyclopropyl-3-piperidyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 261 N-[3-(1-cyclopropyl-4-piperidyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 143 methyl 3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-1-carboxylate 12 methyl 4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-1-carboxylate 25 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)pyrrolidin- 3-yl]phenyl]-1,2,4-triazol-3-amine 473 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 92 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 230 N-[3-fluoro-5-[1-(oxetan-3-yl)pyrrolidin-3-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 268 1-(3,5-difluorophenyl)-N-[3-fluoro-5-[1-(oxetan-3-yl)pyrrolidin- 3-yl]phenyl]-1,2,4-triazol-3-amine 382 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)pyrrolidin-3- yl]phenyl]-1,2,4-triazol-3-amine 260 N-[3-methyl-5-[1-(oxetan-3-yl)pyrrolidin-3-yl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 416 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 160 N-[3-methyl-5-[1-(oxetan-3-yl)-2,5-dihydropyrrol-3-yl]phenyl]- 1-phenyl-1,2,4-triazol-3-amine 18 N-[3-[3-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl]-5-methyl-phenyl]- 1-phenyl-1,2,4-triazol-3-amine 193 1-(3,5-difluorophenyl)-N-[3-[3-fluoro-1-(oxetan-3-yl)pyrrolidin- 3-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 242 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-1-methyl-pyrrolidin-3-ol 23 1-(3,5-difluorophenyl)-N-[3-(3-fluoro-1-methyl-pyrrolidin-3-yl)- 5-methyl-phenyl]-1,2,4-triazol-3-amine 101 (3S)-3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 487 (3R)-3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 248 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 408 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3- piperidyl]phenyl]-1,2,4-triazol-3-amine 180 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-pyrimidin- 4-yl-1,2,4-triazol-3-amine 74 N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-pyrazin-2- yl-1,2,4-triazol-3-amine 449 1-[3-[3-methyl-5-[(1-pyrimidin-4-yl-1,2,4-triazol-3- yl)amino]phenyl]-1-piperidyl]ethanone 515 1-(3,5-difluorophenyl)-N-[3-[4-fluoro-1-(oxetan-3-yl)-4- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 516 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-1-(oxetan-3-yl)piperidin-4-ol 613 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-3,5-dimethyl-oxazolidin-2-one 846 3,5-dimethyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one 658 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]-5-methyl-oxazolidin-2-one 741 5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one 611 (5S)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3,5-dimethyl-oxazolidin-2-one 796 (5R)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3,5-dimethyl-oxazolidin-2-one 603 (5S)-5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one 682 (5R)-5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one 679 (5S)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5-methyl-oxazolidin-2-one 655 (5R)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5-methyl-oxazolidin-2-one 755 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4-methyl- 2-pyridyl]piperidin-3-ol

Compounds of the invention may be prepared as generally outlined in Scheme K, where R², R³, R⁴⁰, and R¹⁰⁰ are as described for Scheme A. The methods of Scheme K are useful for preparing compounds where R¹⁰⁰ is attached by reduction amination or acylation of an amine group. The methods of Scheme K may also be applied to other variations of L¹ with G¹ to G⁵ that bond to the parent molecular moiety through a nitrogen atom.

Example 22 Preparation of N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 26)

Using the general synthetic scheme outlined in Scheme K and the experimental procedures listed above in Example 22, the following compounds were prepared:

Cmpd No. IUPAC Name 144 1-[4-[3-(difluoromethyl)-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]ethanone 62 N-[3-(difluoromethyl)-5-piperazin-1-yl-phenyl]-1-phenyl-1,2,4- triazol-3-amine 446 1-(2-chlorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine

Compounds of the invention may be prepared as generally outlined in Scheme L, where R¹, R², R³, R⁴⁰, and X¹ are as described in Scheme A. R⁷⁰ and R⁸⁰ represent various substituted R¹ groups arrived at by the indicated synthetic manipulations.

Example 23 Preparation of 2-cyclopropyl-N-(1-(3,4-difluorophenyl)-1H-1,2,4-triazol-3-yl)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-amine (Compound 150)

Preparation of 2-cyclopropyl-N-(1-(3,4-difluorophenyl)-1H-1,2,4-triazol-3-yl)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-amine (Compound 150)

A t-BuOH (5 mL) mixture of 2-cyclopropyl-6-tetrahydropyran-4-yl-pyridin-4-amine 23b, (130 mg, 0.56 mmol), 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole (287 mg, 1.11 mmol), t-BuXPhos Palladacycle (72 mg, 0.111 mmol) and t-BuOK (93 mg, 0.83 mmol) was stirred at 45° C. for 1 h. LCMS indicated the reaction was 90% completed so the reaction mixture was stirred at 45° C. for one more hour. LCMS was the same as before. Work up: the reaction mixture was filtered through Celite, to the filtrate was added EA and brine, the organic phase was dried over MgSO₄, filtered, concentrated down and purified by Isco (40 g Gold) silica gel column with HEP and EA, the product was eluted with 30% HEP and 70% EA and give 76 mg (32%) of 2-cyclopropyl-N-(1-(3,4-difluorophenyl)-1H-1,2,4-triazol-3-yl)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-amine, cmpd 150. ¹H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.26 (d, J=2.2 Hz, 2H), 7.17 (d, J=2.0 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H), 6.95-6.78 (m, 2H), 4.11 (d, J=10.9 Hz, 2H), 3.58 (td, J=11.3, 3.5 Hz, 2H), 2.97-2.79 (m, 1H), 2.03 (td, J=8.0, 4.0 Hz, 1H), 1.96-1.80 (m, 4H), 1.11-1.02 (m, 2H), 0.97 (ddd, J=10.3, 6.4, 3.9 Hz, 2H) ppm. ESI-MS m/z calc. 397.17142. found 398.21; (M+1)⁺; Retention time: 0.61 minutes.

Using the general synthetic scheme outlined in Scheme L and the experimental procedures listed above in Example 23, the following compounds were prepared:

Cmpd No. IUPAC Name 150 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- tetrahydropyran-4-yl-pyridin-4-amine 407 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- tetrahydropyran-4-yl-pyridin-4-amine 3 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- (3,6-dihydro-2H-pyran-4-yl)pyridin-4-amine 35 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- (3,6-dihydro-2H-pyran-4-yl)pyridin-4-amine 798 N-[3-(2-cyclopropylethynyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 769 N-[3-(2-cyclopropylethynyl)-5-methyl-phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine

Compounds of the invention may be prepared as generally outlined in Scheme M, where R², R⁴, and X¹ are as described herein, and HL¹-R¹ is an amine such that -L¹-R¹, as defined herein, is bonded to the parent molecular moiety through a nitrogen atom. In the indicated example, an N-methyl piperazine moiety serves as L¹-R¹. (a) NMP, 100° C., 12-24 hours; (b) t-BuXPhos Palladacycle, Sodium t-butoxide, 1,4-dioxane, 90° C., 12-24 hours

Example 23A Preparation of N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 486) Preparation of 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-piperazine

1-Bromo-3-fluoro-5-(trifluoromethyl)benzene (1.52 g, 6.26 mmol) was dissolved in NMP (2.0 mL). Methylpiperazine (1.88 g, 2.08 mL, 18.8 mmol) was added and the vial was sealed. Stirred the reaction mixture overnight at 100° C. The reaction mixture was concentrated to an oil. The oil was diluted with DCM (20 ml), the organic phase washed with 50% saturated sodium bicarbonate, passed through a phase separator, and concentrated to dryness to yield 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-piperazine (1.73 g, 83%). ¹H NMR (300 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.18 (s, 2H), 3.30-3.16 (m, 4H), 2.46-2.33 (m, 4H), 2.21 (s, 3H) ppm. ESI-MS m/z calc. 322.02924. found 323.03; (M+1)+; Retention time: 0.62 minutes.

Preparation of N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine (Compound 486)

1-Phenyl-1,2,4-triazol-3-amine (64 mg, 0.4 mmol), sodium tert-butoxide (57.60 mg, 0.5994 mmol), t-BuXPhos Palladacycle (30 mg, 0.4 mmol), and 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-piperazine (129 mg, 0.4 mmol) were weighed into a 20 ml vial. Vacuum was applied to the vial and flushed with nitrogen three times. Dioxane (2 mL) was added and stirred the mixture in a sealed vial at 90° C. overnight. The crude reaction mixture was diluted with dichloromethane (20 ml), and washed with 50% saturated sodium bicarbonate. The organic layer was passed through a phase separator and concentrated to dryness. The residue was diluted with DMSO (2 ml) and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and TFA as a modifier to yield the product as the TFA salt. The pooled desired pure fractions were concentrated to dryness. Diluted combined fractions with DCM and washed with saturated sodium bicarbonate. The organics were passed through a phase separator, acidified with 2M HCl in diethyl ether, and concentrated to dryness to yield the HCl salt of N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine, cmpd 486 (99 mg, 565). ¹H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.89-7.79 (d, 2H), 7.56 (m, 4H), 7.38 (t, J=7.4 Hz, 1H), 6.84 (s, 1H), 3.88 (d, J=9.7 Hz, 2H), 3.51 (m, 2H), 3.19 (m, 4H), 2.85 (s, 3H) ppm. ESI-MS m/z calc. 402.17798. found 403.28; (M+1)+; Retention time: 3.08 minutes.

Example 23B Preparation of N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine (Compound 331)

Preparation of 1-(6-chloro-4-methyl-2-pyridyl)-4-(oxetan-3-yl)piperazine (RG-10a)

2,6-dichloro-4-methyl-pyridine (653 mg, 4.030 mmol), DIEA (625.0 mg, 842 μL, 4.84 mmol), and 1-(oxetan-3-yl)piperazine (704 mg, 4.95 mmol) were combined in a 20 ml vial. Added a stir bar and NMP (4.0 mL) before sealing the vial and heating overnight at 100° C. After 20 h, the reaction was complete. Diluted with DMSO (5 mls), and injected on a C-18 Aq 275 g column and eluted with 0-41% ACN in water with a TFA modifier over 18 minutes. Pooled desired product fractions and concentrated to dryness, then diluted with DCM and minimal methanol to dissolve. Washed with 50% saturated sodium bicarbonate. Passed through a phase separator and concentrated to dryness to yield 1-(6-chloro-4-methyl-2-pyridyl)-4-(oxetan-3-yl)piperazine RG-10a (661 mg, 2.46 mmol, 61%). 1H NMR (300 MHz, DMSO-d6) δ 6.63 (s, 1H), 6.54 (s, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 3.54-3.45 (m, 4H), 3.41 (m, 1H), 2.38-2.26 (m, 4H), 2.21 (s, 3H) ppm. ESI-MS m/z calc. 267.11383. found 268.14. (M+1)+; Retention time: 0.59 minutes.

Preparation of N-[1-(3, 5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine (Compound 331)

1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (123 mg, 0.6270 mmol), t-BuXPhos palladacycle (25 mg, 0.03384 mmol), sodium t-butoxide (100 mg, 1.041 mmol) and 1-(6-chloro-4-methyl-2-pyridyl)-4-(oxetan-3-yl)piperazine RG-10a (171 mg, 0.6351 mmol) were dissolved into dry t-BuOH (1.75 mL) and dry dioxane (600 μL). Purged with N₂ for ˜10 minutes. Stirred at 50° C. for 1 h. LC/MS showed no remaining starting material so concentrated to dryness and diluted with 20 ml of DCM. Washed with 10 ml of 50% sat. sodium bicarbonate, passed through a phase separator, and concentrated to dryness. Diluted with DCM (10 ml, poor solubility) and passed through a plug of florisil then concentrated to dryness. Diluted with 8 mls of DMSO and injected on the C18 50 g Aq column eluting with 0-60% ACN in water over 17 minutes with a TFA modifier. Combined desired fractions, concentrated to dryness and diluted with DCM. Washed with 50% sat. sodium bicarbonate, passed through a phase separator, and concentrated to dryness. Diluted with 5 mls of DCM and injected on a 40 g Si gold column eluting with 0-100% (ethyl acetate (10% methanol)) in heptane over 22 minutes. Combined desired fractions and concentrated to dryness to give N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 331 (125 mg, 0.289 mmol, 46%) 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.18 (s, 1H), 7.64 (dd, J=8.6, 2.2 Hz, 2H), 7.32-7.20 (m, 1H), 6.97 (s, 1H), 6.17 (s, 1H), 4.57 (t, J=6.5 Hz, 2H), 4.48 (t, J=6.1 Hz, 2H), 3.52 (m, 4H), 3.47-3.37 (m, 1H), 2.33 (m, 4H), 2.23 (s, 3H) ppm. ESI-MS m/z calc. 427.1932. found 428.29. (M+1)+; Retention time: 0.62 minutes.

Using the general synthetic scheme outlined in Scheme M and the experimental procedures for Example 23A and 23B, the following compounds were prepared:

Cmpd No. IUPAC Name 393 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2,6-dimorpholino- pyridin-4-amine 319 2,6-dimorpholino-N-(1-phenyl-1,2,4-triazol-3-yl)pyridin-4-amine 265 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6- morpholino-pyridin-4-amine 153 N-[3-(4-cyclopropylpiperazin-1-yl)-5-(difluoromethyl)phenyl]-1- (2-fluoro-4-pyridyl)-1,2,4-triazol-3-amine 348 N-[3-(4-cyclopropylpiperazin-1-yl)-5-(difluoromethyl)phenyl]-1- phenyl-1,2,4-triazol-3-amine 209 N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]- 1-(3-pyridyl)-1,2,4-triazol-3-amine 82 N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]- 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 189 N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]- 1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-amine 163 4-[3-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]-1H-pyridin-2-one 475 1-(3,5-difluorophenyl)-N-[3-morpholino-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 63 1-(3,5-difluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 366 N-[3-morpholino-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 257 1-(3-fluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 4 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-2-yl]cyclobutanol 123 2-[(2S)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-(trifluoromethyl)phenyl]piperazin-2-yl]propan-2-ol 331 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 547 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1-phenyl-1,2,4-triazol- 3-yl)-4-(trifluoromethyl)pyridin-2-amine 545 N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 546 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 540 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 560 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- morpholino-pyridin-2-amine 554 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- (trifluoromethyl)-2-pyridyl]-N-ethyl-piperazine-1-carboxamide 562 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(4- tetrahydrofuran-3-ylpiperazin-1-yl)pyridin-2-amine 564 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- tetrahydrofuran-3-ylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2- amine 555 1-[4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- (trifluoromethyl)-2-pyridyl]piperazin-1-yl]ethanone 569 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4-methyl- 2-pyridyl]-4-methyl-piperidin-4-ol 571 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3-oxa- 6-azaspiro[3.3]heptan-6-yl)pyridin-2-amine 570 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(7-oxa- 2-azaspiro[3.4]octan-2-yl)pyridin-2-amine 537 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 556 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-piperazin-1-yl-4- (trifluoromethyl)pyridin-2-amine 567 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-[4-(oxetan-3- yl)piperazin-1-yl]-6-(trifluoromethyl)pyridin-2-amine 568 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3-fluoro-1- piperidyl)-4-methyl-pyridin-2-amine 572 2-[1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]azetidin-3-yl]propan-2-ol 565 ethyl 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]piperidine-4-carboxylate 563 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[3- (oxetan-3-yl)azetidin-1-yl]pyridin-2-amine 548 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(2-pyridyl)-1,2,4-triazol- 3-yl]-4-(trifluoromethyl)pyridin-2-amine 538 N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 557 tert-butyl 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-4-(trifluoromethyl)-2-pyridyl]piperazine-1- carboxylate 821 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4-methyl- 2-pyridyl]azetidine-3-carbonitrile 619 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 654 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4-ethylpiperazin- 1-yl)-4-(trifluoromethyl)pyridin-2-amine 760 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-[4-(oxetan-3- yl)piperazin-1-yl]-6-(trifluoromethyl)pyridin-4-amine 732 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]- 6-(3-morpholinoazetidin-1-yl)pyridin-2-amine 847 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-fluoro-4-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 815 [1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]-3-piperidyl]methanol 755 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4-methyl- 2-pyridyl]piperidin-3-ol 764 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3-methoxy-1- piperidyl)-4-methyl-pyridin-2-amine 616 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-methyl-4-(3- morpholinoazetidin-1-yl)pyridin-2-amine 786 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[3- (methoxymethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 787 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-[(3S)- tetrahydrofuran-3-yl]piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-amine 672 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-[(3R)- tetrahydrofuran-3-yl]piperazin-1-yl]-4-(trifluoromethyl)pyridin- 2-amine 777 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]- 6-(2-oxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-amine 740 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- [(3S)-tetrahydrofuran-3-yl]piperazin-1-yl]pyridin-2-amine 673 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- [(3R)-tetrahydrofuran-3-yl]piperazin-1-yl]pyridin-2-amine 601 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3- morpholinoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2-amine 729 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(methoxymethyl)-1-piperidyl]pyridin-2-amine 839 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-(trifluoromethyl)pyridin-2- amine 674 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-morpholino-4- (trifluoromethyl)pyridin-2-amine 733 6-chloro-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 650 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methylpiperazin-1-yl)-4-[4-(oxetan-3-yl)piperazin-1- yl]pyridin-2-amine 726 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4,6-bis[4-(oxetan- 3-yl)piperazin-1-yl]pyridin-2-amine 712 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1-pyrazin-2-yl-1,2,4-triazol- 3-yl)-4-(trifluoromethyl)pyridin-2-amine 770 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-morpholino-4- (trifluoromethyl)pyridin-2-amine 680 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 719 4-(difluoromethyl)-6-(3-morpholinoazetidin-1-yl)-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 578 4-methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 576 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1- pyrazin-2-yl-1,2,4-triazol-3-yl)pyridin-2-amine 867 4-(difluoromethyl)-6-morpholino-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 837 4-methyl-6-morpholino-N-[1-[3-(trifluoromethyl)phenyl]-1,2,4- triazol-3-yl]pyridin-2-amine 853 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-4-carbonitrile 607 2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-4-carbonitrile 848 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4-methyl-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 768 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4-methyl-6- (3-morpholinoazetidin-1-yl)pyridin-2-amine 664 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-N-methyl-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridine-4-carboxamide 580 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4-(3- methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 756 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-(3-morpholinoazetidin-1-yl)pyridin-2-amine 718 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 636 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-6-(3- morpholinoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2-amine 716 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 689 N6-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4-methyl- N2-tetrahydrofuran-3-yl-pyridine-2,6-diamine 600 4-methyl-N2-tetrahydrofuran-3-yl-N6-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridine-2,6-diamine 614 N6-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-N2- tetrahydrofuran-3-yl-pyridine-2,6-diamine 807 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-(trifluoromethyl)pyridin-2- amine 645 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-[4-(methoxymethyl)-1-piperidyl]pyridin-2-amine 795 4-(difluoromethyl)-6-[4-(methoxymethyl)-1-piperidyl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 849 4-(difluoromethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 639 N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4- methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 610 4-methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 599 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methoxy-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 612 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-fluoro-4-(3- morpholinoazetidin-1-yl)pyridin-2-amine 660 6-chloro-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-(3- morpholinoazetidin-1-yl)pyridin-2-amine 625 4-(methoxymethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 823 4-(difluoromethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-6- [4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 789 2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-N-methyl-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridine-4-carboxamide 758 N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4-methoxy-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 621 N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 749 N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4-methyl-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 728 N-[1-(4-fluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 675 methyl 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6- morpholino-pyridine-4-carboxylate 859 N-[1-(3-chloro-4-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 579 4-(1,1-difluoroethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 806 4-(difluoromethyl)-N-[1-(4-fluorophenyl)-1,2,4-triazol-3-yl]-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 685 4-(1,1-difluoroethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 860 4-(1,1-difluoroethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-6- [4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 713 [2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]-4-pyridyl]methanol

Compounds of the invention may be prepared as generally outlined in Scheme N, where R², R⁴, and X¹ are as described herein, and HL¹-R¹ is an amine such that -L¹-R¹, as defined herein, is bonded to the parent molecular moiety through a nitrogen atom.

Example 24 Preparation of N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4-amine (Compound 365)

Preparation of 2-chloro-6-(4-methylpiperazin-1-yl)pyridin-4-amine (24A)

A mixture of dioxane (100 mL), 2,6-dichloropyridin-4-amine (4.89 g, 30 mmol), 1-methylpiperazine (15 g, 150 mmol) and DIEA (11.6 g, 15.7 mL, 90 mmol) was stirred at 130° C. in a Qian cap pressure bottle for 4 days. LCMS indicated that the reaction was 80% complete so the reaction was worked up. Work up: the reaction mixture was cooled to RT, EtOAc was added and brine, the organic phase was dried over MgSO₄, filtered, concentrated down and the crude product was purified by Isco (275 g Gold amine column) eluting with EA and heptanes. The product was eluted with 70% EA and 30% heptanes to give 2-chloro-6-(4-methylpiperazin-1-yl)pyridin-4-amine, 24A (2.42 g, 35%). ¹H NMR (400 MHz, CDCl3) δ 6.02 (d, J=1.6 Hz, 1H), 5.72 (d, J=1.6 Hz, 1H), 4.05 (s, 2H), 3.54-3.44 (m, 4H), 2.54-2.45 (m, 4H), 2.34 (s, 3H) ppm. ESI-MS m/z calc. 226.09853. found 227.14; (M+1)⁺; Retention time: 0.45 minutes.

Preparation of 2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4-amine (24B)

To a degassed THF (30 mL) solution of 2-chloro-6-(4-methylpiperazin-1-yl)pyridin-4-amine(1) (1.16 g, 5 mmol) was added palladiumtriphenylphosphane (231 mg, 0.20 mmol) and chloro(methyl)zinc (15 mL of 2 M soln, 30 mmol) and the reaction mixture was refluxed in a pressure bottle for 2 days. LCMS indicated the reaction was completed. Work up: the reaction mixture was cooled to RT, filtered through Celite and concentrated down. To the crude mixture was added 200 ml water, the mixture was stirred for 3 h until all catalyst had precipitated out. Catalyst was filtered off, the aq phase was extracted with EA (70 ml×2), the organic phase was dried over MgSO₄, filtered and concentrated down and used as it is. It gave crude 2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4-amine (24B) (500 mg, 35%. ¹H NMR (400 MHz, CD3OD) δ 6.00-5.91 (m, 1H), 5.80 (dd, J=7.6, 1.5 Hz, 1H), 3.42-3.31 (m, 4H), 2.58-2.48 (m, 4H), 2.31 (d, J=3.8 Hz, 3H), 2.20 (s, 3H) ppm. ESI-MS m/z calc. 206.15315. found 207.15; (M+1)⁺; Retention time: 0.27 minutes.

Preparation of N-(1-(3,5-difluorophenyl)-1H-1,2,4-triazol-3-yl)-2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4-amine (Compound 365)

To a t-BuOH (5 mL) mixture of 2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4-amine 24B (100 mg, 0.485 mmol), 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole 24C (189 mg, 0.727 mmol) and t-BuXPhos Palladacycle (63 mg, 0.097 mmol) was added t-BuOK (163 mg, 1.45 mmol) at 45° C., and the reaction mixture was stirred at 45° C. for 1 h. LCMS indicated desired product only. Work up: to the reaction mixture was added EA and brine, the organic phase was dried with MgSO₄, filtered, concentrated down and purified by Isco 40 g Gold silica gel column with DCM and MeOH. The product was eluted with 15% MeOH and 85% DCM and gave N-(1-(3,5-difluorophenyl)-1H-1,2,4-triazol-3-yl)-2-methyl-6-(4-methylpiperazin-1-yl)pyridin-4-amine, cmpd 365 (94 mg, 47%). ¹H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.21 (s, 1H), 7.70-7.53 (m, 2H), 7.28 (tt, J=9.3, 2.3 Hz, 1H), 6.94 (s, 1H), 6.72 (s, 1H), 3.50-3.37 (m, 4H), 2.44-2.33 (m, 4H), 2.25 (s, 3H), 2.22 (s, 3H) ppm. ESI-MS m/z calc. 385.18265. found 386.19. (M+1)⁺; Retention time: 0.52 minutes.

Using the general synthetic scheme outlined in Scheme N and the experimental procedures listed above in Example 24, the following compounds were prepared:

Cmpd No. IUPAC Name 367 2-chloro-6-(4-methylpiperazin-1-yl)-N-(1-phenyl-1,2,4-triazol-3- yl)pyridin-4-amine 477 2-chloro-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methylpiperazin-1-yl)pyridin-4-amine 135 2-chloro-6-morpholino-N-(1-phenyl-1,2,4-triazol-3-yl)pyridin-4- amine 100 2-chloro-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 251 N-(3-morpholino-5-tetrahydropyran-4-yl-phenyl)-1-phenyl-1,2,4- triazol-3-amine 57 (2R)-3-methyl-2-[4-[6-methyl-4-[(1-phenyl-1,2,4-triazol-3- yl)amino]-2-pyridyl]piperazin-2-yl]butan-2-ol 345 2-chloro-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 106 2-chloro-N-[1-(3-methoxyphenyl)-1,2,4-triazol-3-yl]-6-(1- piperidyl)pyridin-4-amine 145 2-chloro-N-[1-(3-methoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 365 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-(4- methylpiperazin-1-yl)pyridin-4-amine 263 N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-(4- methylpiperazin-1-yl)pyridin-4-amine 156 2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-phenyl-1,2,4-triazol- 3-yl)pyridin-4-amine 430 2-(4-fluoro-1-piperidyl)-6-methyl-N-(1-phenyl-1,2,4-triazol-3- yl)pyridin-4-amine 457 N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-(4-fluoro-1- piperidyl)-6-methyl-pyridin-4-amine

Compounds of the invention may be prepared as generally outlined in Scheme O, where R¹, R², R³, R⁴⁰, and X¹ are as described herein. The methods of Scheme O are useful for the preparation of compounds where L¹ is an oxygen atom. R¹ groups, or protected derivatives thereof, may be subjected to further synthetic manipulation (e.g., deprotection, reductive amination, acylation, etc.) to arrive at additional compounds of the invention.

Example 25 Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine (Compound 433)

Preparation of (tert-butyl 4-(3-methyl-5-nitro-phenoxy)piperidine-1-carboxylate (JW-9a)

3-methyl-5-nitro-phenol (4.0 g, 26.1 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (5.3 g, 26.1 mmol) and triphenylphosphane (6.9 g, 6.1 mL, 26 mmol) were mixed in THF (40 mL) and isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (5.3 g, 26 mmol) was added into the reaction. The mixture was stirred at RT overnight, then diluted with water and extracted with DCM (100 ml×2). The combined organic layer was dried and concentrated. The crude product was purified on silica gel eluting with EtOAc:Hexanes (10-30%) to afford 5.98 g (68%) of JW-9a, (tert-butyl 4-(3-methyl-5-nitro-phenoxy)piperidine-1-carboxylate.

Preparation of 4-(3-methyl-5-nitro-phenoxy)piperidine (JW-9b)

tert-Butyl 4-(3-methyl-5-nitro-phenoxy)piperidine-1-carboxylate (JW-9a) (5.1 g, 15.2 mmol) was dissolved in DCM (20 mL) and TFA (10 mL) was added into the solution. The reaction was stirred at room temperature for 30 minutes and LCMS showed that the reaction was complete. The solvent was removed and the crude was dissolved in DCM (50 ml) and washed with NaHCO₃ (aq.) and brine. The organic layer was dried and concentrated to afford 2.65 g (53%) of JW-9b, 4-(3-methyl-5-nitro-phenoxy)piperidine in 53% yield. ESI-MS m/z calc. 236.12. found 237.45; (M+1)⁺; Retention time: 0.60 minutes.

Preparation of 4-(3-methyl-5-nitro-phenoxy)-1-(oxetan-3-yl)piperidine (JW-9c)

4-(3-methyl-5-nitro-phenoxy)piperidine (JW-9b) (2.5 g, 10.6 mmol) and oxetan-3-one (1.52 g, 21.1 mmol) were mixed in DCE (25 mL) and the reaction was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (4.5 g, 21.2 mmol) was added into the reaction and the reaction was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction was quenched with 1N NaOH (aq.) and extracted with DCM. The organic layer was dried and concentrated. The crude was purified on silica gel using 10-90% EtOAc:Hexanes to afford 1.82 g (405) of JW-9c, 4-(3-methyl-5-nitro-phenoxy)-1-(oxetan-3-yl)piperidine. ESI-MS m/z calc. 292.14. found 293.39; (M+1)⁺; Retention time: 0.60 minutes.

Preparation of 3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]aniline (JW-9d)

To a 250 ml RBF was added Pd on carbon (10% by weight, 62 mg) under N2 and EtOH (20 mL) was added. 4-(3-Methyl-5-nitro-phenoxy)-1-(oxetan-3-yl)piperidine (JW-9c) (1.72 g, 5.88 mmol) was added into the reaction and the reaction was stirred at room temperature under H2 with an attached balloon overnight. LCMS showed that the reaction was complete. The catalyst was filtered off and the filtrate was concentrated to afford 1.28 g (83%) of JW-9d, of 3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]aniline. ESI-MS m/z calc. 262.17. found 263.47. (M+1)⁺; Retention time: 0.26 minutes.

Preparation of 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole (JW-1c)

Diacetoxycopper (2.30 g, 12.7 mmol), 3,5-difluorophenyl-boronic acid (1.60 g, 10.1 mmol), 3-bromo-1H-1,2,4-triazole (1.25 g, 8.4 mmol) and 4A molecular sieves (150 mg) were mixed in DCM (50 mL) and pyridine (1.3 mL, 16.9 mmol) was added. The mixture was stirred at RT under air for 3 days. LCMS showed that no starting material remaining and desired product was formed. The reaction was filtered through a plug of Celite via suction and the solid cake was washed with an additional 200 ml DCM. The combined organic layer was washed with 0.1 N aqueous HCl (50 ml×3) and brine (200 ml). The organic layer was concentrated and crude product purified on silica gel (120 g column, dry loading method on celite) using 10-90% EtOAc:Hexanes to afford 1.23 g (50%) of desired product JW-1c, 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole. ¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.78-7.61 (m, 2H), 7.41 (tt, J=9.3, 2.3 Hz, 1H) ppm. ESI-MS m/z calc. 258.96. found 260.05; (M+1)+; Retention time: 0.8 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine (Compound 433)

Sodium t-butoxide (148.6 mg, 1.546 mmol), t-BuXPhos Palladacycle (21 mg, 0.03 mmol), 3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]aniline (JW-9d) (200 mg, 0.77 mmol) and 3-bromo-1-(3,5-difluorophenyl)-1,2,4-triazole (JW-1c) (199 mg, 0.76 mmol) were mixed in t-BuOH (2.5 mL) and the reaction was degassed with N₂ for 30 seconds. The reaction was heated at 60 degrees for 3 hours and LCMS indicated that the reaction was complete. The reaction was cooled to room temperature and water was added to quench the reaction. Brine was added, the mixture was extracted with DCM and the organic layer was dried and concentrated. The crude was purified on reverse phase using 10-90% acetonitrile:water (0.1% TFA) and the desired fraction was converted into free base to afford 15.3 mg (11%) of cmpd 433, 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine. 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.16 (s, 1H), 7.60 (d, J=6.4 Hz, 2H), 7.42-7.20 (m, 2H), 6.83 (s, 1H), 6.28 (s, 1H), 4.53 (t, J=6.5 Hz, 2H), 4.43 (t, J=6.1 Hz, 2H), 4.32 (s, 1H), 3.41 (dd, J=12.6, 6.3 Hz, 1H), 2.58 (s, 2H), 2.22 (s, 3H), 2.15-1.94 (m, 4H), 1.77-1.55 (m, 2H) ppm. ESI-MS m/z calc. 441.19763. found 442.44; (M+1)+; Retention time: 0.65 minutes.

Using the general synthetic scheme outlined in Scheme 0 and the experimental procedures in Example 25, the following compounds were prepared:

Cmpd No. IUPAC Name 304 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 433 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 384 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 410 N-[3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]phenyl]-1- phenyl-1,2,4-triazol-3-amine 201 1-(4-fluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 52 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 239 N-[3-methyl-5-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-phenyl]- 1-phenyl-1,2,4-triazol-3-amine 178 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 391 N-[3-methyl-5-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-phenyl]- 1-phenyl-1,2,4-triazol-3-amine 46 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine 703 1-(3,5-difluorophenyl)-N-(3-methyl-5-tetrahydrofuran-3-yloxy- phenyl)-1,2,4-triazol-3-amine 778 1-(3,4-difluorophenyl)-N-(3-methyl-5-tetrahydrofuran-3-yloxy- phenyl)-1,2,4-triazol-3-amine 805 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenoxy]-1-piperidyl]ethanone 626 1-[4-[3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenoxy]-1-piperidyl]ethanone 620 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 590 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 700 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[(3S)-1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 748 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[(3R)-1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 632 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[(3S)-1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 665 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[(3R)-1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 677 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3-methyloxetan-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 615 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3-methyloxetan-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 671 N-[3-methyl-5-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 812 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2- morpholinoethoxy)phenyl]-1,2,4-triazol-3-amine 845 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2- morpholinoethoxy)phenyl]-1,2,4-triazol-3-amine 575 N-[3-methyl-5-(2-morpholinoethoxy)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 635 1-(3,5-difluorophenyl)-N-(3-methyl-5-tetrahydropyran-3-yloxy- phenyl)-1,2,4-triazol-3-amine 638 1-(3,4-difluorophenyl)-N-(3-methyl-5-tetrahydropyran-3-yloxy- phenyl)-1,2,4-triazol-3-amine 706 N-[3-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 640 N-[3-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-phenyl]-1- (3,4-difluorophenyl)-1,2,4-triazol-3-amine 832 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-pyrazol-1- ylethoxy)phenyl]-1,2,4-triazol-3-amine 698 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2-pyrazol-1- ylethoxy)phenyl]-1,2,4-triazol-3-amine 644 N-[3-methyl-5-(2-pyrazol-1-ylethoxy)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 605 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1-methylpyrazol-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 714 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(1-methylpyrazol-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 648 1-(3,5-difluorophenyl)-N-[3-methyl-5-(tetrahydrofuran-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 865 1-(3,4-difluorophenyl)-N-[3-methyl-5-(tetrahydrofuran-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 627 1-(3,4-difluorophenyl)-N-[3-methyl-5-(tetrahydropyran-4- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 978 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3-tetrahydrofuran- 3-yloxy-phenyl)-1,2,4-triazol-3-amine 913 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 907 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- phenyl-1,2,4-triazol-3-amine 952 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- pyrazin-2-yl-1,2,4-triazol-3-amine 1053 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3-tetrahydrofuran- 3-yloxy-phenyl)-1,2,4-triazol-3-amine 1028 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3-tetrahydrofuran- 3-yloxy-phenyl)-1,2,4-triazol-3-amine 886 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1061 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1009 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3-tetrahydrofuran- 3-yloxy-phenyl)-1,2,4-triazol-3-amine 1055 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3-tetrahydrofuran- 3-yloxy-phenyl)-1,2,4-triazol-3-amine 1002 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- phenyl-1,2,4-triazol-3-amine 1052 N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- phenyl-1,2,4-triazol-3-amine 1094 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5- dimethyl-phenoxy]-1-morpholino-ethanone

Compounds of the invention may be prepared as generally outlined in Scheme P, where R² and R⁴ are as described herein.

Example 26 Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine (Compound 596)

Preparation of 1-(3-bromo-5-methylbenzyl)-4-(oxetan-3-yl)piperazine (YL-20a)

To a solution of 3-bromo-5-methyl-benzaldehyde (7.50 g, 37.68 mmol), 1-(oxetan-3-yl)piperazine (4 g, 28.13 mmol) and acetic acid (3 mL, 52.75 mmol) in dichloromethane (150 mL) was added NaBH(OAc)₃ (11.98 g, 56.52 mmol) carefully. The mixture was stirred for 4 h. LCMS showed desired product. The reaction was diluted with DCM and slowly quenched with MeOH and sat. NaHCO₃ (50 mL). After separation, the organic layer was washed with water, sat NaCl and dried over sodium sulfate, filtered and concentrated to give 1-[(3-bromo-5-methyl-phenyl)methyl]-4-(oxetan-3-yl)piperazine YL-20a (7.3 g, 59.6%) ¹H NMR (300 MHz, CDCl₃) δ 7.29 (s, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 4.82-4.50 (m, 4H), 3.61-3.48 (m, 1H), 3.47 (d, J=5.7 Hz, 2H), 2.51 (m, 4H), 2.39 (m, 4H), 2.33 (s, 3H) ppm. ESI-MS m/z calc 324.08. found 325.48. (M+1)⁺; Retention time: 0.66 minutes.

Preparation of 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine (Compound 596)

1-[(3-bromo-5-methyl-phenyl)methyl]-4-(oxetan-3-yl)piperazine YL-20a (290 mg, 0.89 mmol), 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (JW-1c) (216 mg, 0.99 mmol), and sodium t-butoxide (174 mg, 1.81 mmol) were suspended in dioxane (13 mL) and purged with N₂ for several minutes before addition of t-BuXPhos Palladacycle (52 mg, 0.076 mmol). The mixture was microwaved at 125° C. for 45 minutes. The reaction was quenched with MeOH (2 mL) and diluted with DCM. After filtration (Florisil/10 g), the excess solvent was pumped down. ISCO purification (40 g silica; 0% to 10% of MeOH in DCM) followed by DCM/MeOH trituation gave cmpd 596 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine (180 mg, 43.5%). ¹H NMR (300 MHz, CDCl₃) δ 8.33 (s, 1H), 7.39 (s, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 6.89-6.75 (m, 2H), 6.70 (s, 1H), 4.75-4.53 (m, 4H), 3.62-3.44 (m, 3H), 2.59 (m, 4H), 2.40 (m, 7H) ppm. ESI-MS m/z calc. 440.21. found 441.67; (M+1)+; Retention time: 0.68 minutes.

Example 27 Preparation of N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (Compound 1100)

Preparation of 1-(3-bromo-5-methyl-phenyl)piperazine (YL-19a)

A mixture of 3-bromo-5-methyl-aniline (5 g, 26.87 mmol) and 2-chloro-N-(2-chloroethyl)ethanamine (Hydrochloric Acid (1)) (5.28 g, 29.56 mmol) in butan-1-ol (100 mL) was refluxed at 125° C. for 16 h. After filtration, the solids were collected, washed with n-butanol and dried. The solid was dissolved in EtOAc (200 mL) and treated with sat. Na₂CO₃ (40 mL). The organic layer was collected, then excess solvent was removed in vacuo. ISCO purification (40 g silica; 0% to 10% to 30% of MeOH in DCM) gave 1-(3-bromo-5-methyl-phenyl)piperazine YL-19a (2.7 g, 39.4%). ¹H NMR (300 MHz, CDCl₃) δ 6.86 (d, J=1.9 Hz, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 3.50 (s, 1H), 3.14 (dd, J=6.3, 3.6 Hz, 4H), 3.02 (dd, J=6.2, 3.6 Hz, 4H), 2.29 (d, J=0.4 Hz, 3H) ppm. ESI-MS m/z calc. 254.04. found 255.32; (M+1)+; Retention time: 0.64 minutes.

Preparation of 1-(3-bromo-5-methyl-phenyl)-4-(3-deuteriooxetan-3-yl)piperazine (YL-19b)

To a solution of 1-(3-bromo-5-methyl-phenyl)piperazine, YL-19a (640 mg, 2.38 mmol), oxetan-3-one (1.37 g, 19.02 mmol) and acetic acid (676 μL, 11.89 mmol) in dichloromethane (21 mL) was added NaBD(OAc)₃ (2.52 g, 11.89 mmol) carefully. CD₃OD (2 mL) was added to the above mixture. The reaction mixture was stirred at RT for 18 h. Reaction was diluted with DCM and slowly quenched with MeOH and sat. NaHCO₃ (50 mL). After separation, the organic layer was washed with water, sat NaCl and dried. The excess solvent was removed in vacuo and the crude product purified by ISCO purification (12 g silica; 0% to 5% to 10% of MeOH in DCM) to give 1-(3-bromo-5-methyl-phenyl)-4-(3-deuteriooxetan-3-yl)piperazine YL-19b (300 mg, 58.4%). ¹H NMR (300 MHz, CDCl₃) δ 6.90-6.79 (m, 2H), 6.65 (s, 1H), 4.69 (q, J=6.3 Hz, 4H), 3.29-3.16 (m, 4H), 2.57-2.44 (m, 4H), 2.30 (s, 3H) ppm. ESI-MS m/z calc. 311.07. found 312.38; (M+1)+; Retention time: 0.67 minutes.

Preparation of N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (Compound 1100)

A mixture of 1-(3-bromo-5-methyl-phenyl)-4-(3-deuteriooxetan-3-yl)piperazine YL-19b (150 mg, 0.48 mmol), 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine (113 mg, 0.58 mmol) and sodium t-butoxide (115 mg, 1.20 mmol) in dioxane (6.0 mL) was purged with N₂ for several minutes. t-BuXPhos Palladacycle (31 mg, 0.048 mmol) was added. The mixture was microwaved at 120° C. for 35 minutes. The reaction was quenched with MeOH (2 mL) and diluted with DCM. After filtration (Florisil/5 g), the excess solvent was pumped down. ISCO purification (12 g silica; 0% to 5% to 10% of MeOH in DCM) followed by ether trituration gave N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine, Cmpd 1110 (120 mg, 55.5%). ¹H NMR (300 MHz, CDCl₃) δ 8.31 (s, 1H), 7.25 (dd, J=7.8, 2.0 Hz, 2H), 7.12 (s, 1H), 6.87-6.73 (m, 2H), 6.66 (s, 1H), 6.43 (s, 1H), 4.80-4.61 (m, 4H), 3.40-3.21 (m, 4H), 2.64-2.48 (m, 4H), 2.35 (s, 3H) ppm. ESI-MS m/z calc. 427.20. found 428.49; (M+1)+; Retention time: 0.7 minutes.

Deuterium compounds of the present invention may also be prepared as generally outlined in Scheme Q above, where X¹, X², X³, L¹, R¹ R², and R⁴ are as described herein.

Using the general synthetic scheme outlined in Scheme Q the following compounds were prepared:

Cmpd No. IUPAC Name 1088 N-[5-deuterio-1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 1089 N-[5-deuterio-1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (oxetan-3-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 1090 N-[5-deuterio-1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 1093 2-cyclopropyl-N-[5-deuterio-1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-6-morpholino-pyridin-4-amine

Compounds of the invention may be prepared as generally outlined in Scheme R, where L¹, R¹, R² and R⁴ are as described herein.

TABLE 3 Analytical Data LC/MS Ret. Cmpd LC/MS Time No. (M + H) (min) ¹H-NMR 1 428.19 0.51 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.21 (s, 1H), 7.63 (dd, J = 8.3, 2.0 Hz, 2H), 7.29 (dd, J = 10.3, 8.1 Hz, 1H), 6.92 (s, 1H), 6.74 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.44 (dd, J = 11.3, 5.5 Hz, 5H), 2.40-2.31 (m, 4H), 2.26 (s, 3H) ppm. 2 372.19 0.76 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.26 (dd, J = 7.7, 2.0 Hz, 2H), 6.83-6.59 (m, 4H), 5.97 (d, J = 8.7 Hz, 1H), 4.37 (dt, J = 10.7, 5.2 Hz, 1H), 4.17-4.11 (m, 2H), 3.75 (dt, J = 28.4, 14.3 Hz, 2H), 3.39-3.35 (m, 3H), 2.32 (d, J = 6.4 Hz, 3H) ppm. 3 396.18 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.15 (s, 1H), 8.01 (d, J = 11.3 Hz, 1H), 7.80-7.62 (m, 2H), 7.42 (d, J = 4.1 Hz, 2H), 6.65 (s, 1H), 4.26 (s, 2H), 3.81 (t, J = 5.4 Hz, 2H), 2.47-2.37 (m, 2H), 2.05 (d, J = 16.4 Hz, 1H), 0.96-0.80 (m, 4H) ppm. 4 495.18 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.61 (dd, J = 8.2, 2.0 Hz, 2H), 7.56 (s, 1H), 7.46 (s, 1H), 7.29 (td, J = 9.2, 2.2 Hz, 1H), 6.87 (s, 1H), 3.90 (t, J = 12.9 Hz, 2H), 3.58-3.53 (m, 1H), 3.33-3.16 (m, 2H), 3.11-2.94 (m, 2H), 2.48-2.33 (m, 2H), 2.08 (m, 2H), 1.73 (m, 1H), 1.66-1.54 (m, 1H) ppm. 5 447.19 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.18 (s, 1H), 7.59 (dd, J = 8.5, 2.1 Hz, 2H), 7.32-7.22 (m, 1H), 7.16 (d, J = 21.6 Hz, 2H), 6.52 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.45 (dt, J = 12.7, 6.2 Hz, 2H), 3.19 (dd, J = 10.5, 5.4 Hz, 4H), 2.45-2.36 (m, 4H) ppm. 6 350.36 0.68 1H NMR (300 MHz, DMSO-d6) δ 9.13-9.03 (m, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 6.84 (d, J = 18.2 Hz, 1H), 6.15 (s, 1H), 3.46 (dd, J = 18.0, 9.8 Hz, 2H), 3.35-3.17 (m, 2H), 2.31-2.17 (m, 3H), 1.95 (dd, J = 18.0, 9.6 Hz, 2H), 1.44-1.32 (m, 3H) ppm. 7 348 0.27 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.78-7.61 (m, 2H), 7.53 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 6.75 (s, 1H), 6.65 (d, J = 5.8 Hz, 2H), 5.94 (s, 1H), 4.87 (s, 4H), 4.07 (s, 4H), 2.32 (s, 3H) ppm. 8 372.51 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.15 (s, 1H), 7.70-7.60 (m, 2H), 7.24 (t, J = 9.3 Hz, 1H), 6.95 (s, 1H), 6.51 (s, 1H), 5.95 (s, 1H), 5.78-5.66 (m, 1H), 3.97-3.86 (m, 2H), 3.82 (t, J = 7.7 Hz, 1H), 3.73 (m, 1H), 3.55 (m, 1H), 2.22 (m, 1H), 2.15 (s, 3H), 1.81 (m, 1H) ppm. 9 419.16 0.61 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.38 (d, J = 7.2 Hz, 1H), 6.87 (s, 1H), 6.76 (s, 1H), 6.61 (s, 1H), 3.99 (d, J = 7.6 Hz, 4H), 3.69 (s, 4H), 1.89 (s, 1H), 1.82-1.69 (m, 4H), 1.02 (s, 2H), 0.85 (s, 2H) ppm. 10 405.4 0.86 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.75-7.66 (m, 2H), 7.59-7.49 (m, 2H), 7.42-7.34 (m, 1H), 7.31 (d, J = 1.5 Hz, 2H), 6.74 (s, 1H), 6.69 (s, 1H), 4.19-4.05 (m, 4H), 3.57 (td, J = 11.4, 3.1 Hz, 4H), 2.79 (ddd, J = 15.7, 10.4, 4.9 Hz, 2H), 1.98-1.78 (m, 8H) ppm. 11 376.38 0.62 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.66-7.55 (m, 2H), 7.49-7.36 (m, 2H), 7.31-7.24 (m, 1H), 7.12-6.99 (m, 2H), 6.71 (s, 1H), 6.32 (s, 1H), 4.41 (s, 4H), 3.08 (dd, J = 6.6, 4.6 Hz, 4H), 2.24 (s, 3H), 1.94 (dd, J = 6.6, 4.6 Hz, 4H) ppm. 12 392 0.88 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.77-7.60 (m, 2H), 7.50 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.21 (s, 2H), 6.68 (s, 1H), 6.63 (s, 1H), 4.29 (s, 2H), 3.72 (s, 3H), 2.87 (s, 2H), 2.74-2.55 (m, 1H), 2.35 (s, 3H), 1.87 (d, J = 12.8 Hz, 2H), 1.66 (d, J = 14.7 Hz, 3H) ppm. 13 404 0.52 1H NMR (300 MHz, Acetone-d6) δ 9.10 (s, 1H), 8.85 (s, 1H), 8.71 (dd, J = 4.7, 1.6 Hz, 2H), 7.84 (dd, J = 4.7, 1.6 Hz, 2H), 7.66 (s, 1H), 7.54 (s, 1H), 6.82 (s, 1H), 3.41-3.23 (m, 4H), 2.64-2.49 (m, 4H), 2.29 (s, 3H) ppm. 14 423.24 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.02 (s, 1H), 7.93-7.75 (m, 2H), 7.43 (dd, J = 12.1, 5.5 Hz, 2H), 7.15 (s, 1H), 6.93 (s, 1H), 6.33 (s, 1H), 4.71-4.52 (m, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.54-3.38 (m, 1H), 3.15 (s, 4H), 2.53 (d, J = 9.7 Hz, 2H), 2.35 (d, J = 41.2 Hz, 4H), 1.26-1.11 (m, 3H) ppm. 15 423 0.67 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.44 (dd, J = 12.5, 6.1 Hz, 3H), 7.02 (ddd, J = 8.2, 5.1, 2.2 Hz, 2H), 6.76-6.60 (m, 2H), 5.97 (s, 1H), 4.00 (t, J = 6.9 Hz, 2H), 3.75 (dd, J = 10.1, 5.1 Hz, 6H), 3.43-3.22 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 2.45 (s, 4H), 1.24 (t, J = 7.6 Hz, 4H) ppm. 16 424.48 0.65 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 6.86 (s, 1H), 6.71 (s, 1H), 6.49 (s, 1H), 4.77-4.65 (m, 4H), 3.67-3.55 (m, 1H), 2.66 (q, J = 7.6 Hz, 2H), 2.60-2.49 (m, 4H), 1.29 (t, J = 7.6 Hz, 3H) ppm. 17 469.44 0.72 1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.17 (s, 1H), 7.69-7.51 (m, 2H), 7.38-7.16 (m, 2H), 7.07 (s, 1H), 6.53 (d, J = 10.5 Hz, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.67-3.39 (m, 1H), 3.24-3.08 (m, 4H), 2.39 (dd, J = 26.2, 21.4 Hz, 4H), 1.28 (s, 9H) ppm. 18 394.23 0.59 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.09 (s, 1H), 7.85 (dd, J = 8.6, 1.0 Hz, 2H), 7.68 (s, 1H), 7.56 (t, J = 8.0 Hz, 2H), 7.35 (dd, J = 9.0, 5.7 Hz, 2H), 6.75 (s, 1H), 4.61 (td, J = 6.5, 1.6 Hz, 2H), 4.52 (dd, J = 10.4, 5.9 Hz, 2H), 3.83-3.72 (m, 1H), 3.19-2.86 (m, 3H), 2.81-2.71 (m, 1H), 2.40-2.22 (m, 5H) ppm. 19 408.25 0.68 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.17 (s, 1H), 7.65 (dd, J = 8.6, 2.1 Hz, 2H), 7.30-7.20 (m, 2H), 7.10 (m, 1H), 6.92-6.86 (m, 2H), 6.47 (s, 1H), 4.37 (s, 2H), 4.09 (t, J = 5.3 Hz, 2H), 3.71 (t, J = 5.3 Hz, 2H), 2.26 (s, 3H) ppm. 20 377.46 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.19 (s, 1H), 9.05 (d, J = 1.2 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 2.6, 1.4 Hz, 1H), 7.15 (s, 1H), 6.92 (s, 1H), 6.33 (s, 1H), 3.16-3.03 (m, 4H), 2.79-2.66 (m, 4H), 2.24 (s, 3H), 1.75-1.56 (m, 1H), 0.52-0.41 (m, 2H), 0.37-0.30 (m, 2H) ppm. 21 363 0.58 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.35 (d, J = 7.4 Hz, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.68 (s, 1H), 6.56 (s, 1H), 3.24-2.96 (m, 4H), 2.72 (dd, J = 12.0, 9.4 Hz, 1H), 2.53 (dd, J = 11.4, 9.6 Hz, 1H), 2.34 (s, 3H), 1.95 (s, 2H), 1.10 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.1 Hz, 3H) ppm. 22 435.3 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.03 (s, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.6, 2.5 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 6.65 (d, J = 1.3 Hz, 1H), 4.18 (d, J = 12.5 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 2.70 (t, J = 11.4 Hz, 2H), 1.79 (td, J = 8.0, 4.0 Hz, 2H), 1.63 (d, J = 13.0 Hz, 2H), 1.55 (m, 1H), 1.23 (dd, J = 18.5, 10.4 Hz, 1H), 1.09 (dd, J = 22.1, 10.1 Hz, 1H), 0.91 (d, J = 6.4 Hz, 3H), 0.80 (ddt, J = 12.4, 9.6, 3.3 Hz, 4H) ppm. 23 388.26 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.19 (s, 1H), 7.74 (s, 1H), 7.63 (m, 2H), 7.32-7.19 (m, 2H), 6.75 (s, 1H), 3.08-2.79 (m, 3H), 2.67 (dd, J = 14.3, 7.1 Hz, 1H), 2.36 (s, 3H), 2.40-2.32 (m, 1H), 2.30 (s, 3H), 2.28-2.22 (m, 1H) ppm. 24 410.25 0.55 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.39 (s, 1H), 7.80 (dt, J = 9.0, 2.3 Hz, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 6.66 (s, 1H), 6.44 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 3.67-3.52 (m, 1H), 3.37-3.21 (m, 4H), 2.61-2.46 (m, 4H), 2.36 (s, 3H) ppm. 25 412.3 0.61 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 2H), 7.52 (s, 1H), 7.29-7.19 (m, 1H), 7.18 (s, 1H), 6.62 (s, 1H), 4.58 (td, J = 6.5, 1.9 Hz, 2H), 4.50 (td, J = 6.0, 1.2 Hz, 2H), 3.69-3.60 (m, 1H), 3.29-3.21 (m, 1H), 2.97 (t, J = 8.4 Hz, 1H), 2.73 (dd, J = 14.9, 7.8 Hz, 1H), 2.59 (td, J = 8.7, 5.6 Hz, 1H), 2.44-2.38 (m, 1H), 2.26 (s, 3H), 1.79 (dt, J = 13.8, 8.3 Hz, 1H) ppm. 26 427.41 0.65 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.73-7.65 (m, 2H), 7.53 (ddd, J = 8.3, 5.3, 1.8 Hz, 2H), 7.38 (ddd, J = 8.7, 4.6, 1.2 Hz, 2H), 7.17 (s, 1H), 6.86 (s, 1H), 6.63 (dd, J = 67.7, 45.7 Hz, 2H), 4.72 (p, J = 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.41-3.24 (m, 4H), 2.61-2.48 (m, 4H) ppm. 27 354.03 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.04 (s, 1H), 7.89 (s, 2H), 7.40 (t, J = 8.8 Hz, 3H), 6.99 (d, J = 39.5 Hz, 1H), 6.54 (s, 1H), 3.84 (s, 4H), 3.22 (s, 4H), 2.26 (s, 3H) ppm. 28 403 0.66 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.56 (s, 1H), 8.77 (d, J = 2.2 Hz, 1H), 7.88 (dd, J = 14.9, 9.0 Hz, 1H), 7.65 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 16.8 Hz, 2H), 6.15 (d, J = 12.6 Hz, 1H), 3.86-3.60 (m, 2H), 3.44 (s, 4H), 3.31-2.97 (m, 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.29 (s, 1H), 2.19 (s, 1H), 2.19 (s, 1H) ppm. 29 467 0.7 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.16 (s, 1H), 7.60 (dd, J = 8.5, 2.1 Hz, 2H), 7.29 (s, 1H), 7.24 (ddd, J = 9.2, 5.8, 2.2 Hz, 1H), 6.64 (s, 1H), 6.23 (s, 1H), 3.93 (d, J = 8.7 Hz, 1H), 3.53 (dd, J = 11.5, 2.9 Hz, 1H), 3.38 (dt, J = 9.8, 4.9 Hz, 1H), 3.00 (dd, J = 17.7, 9.5 Hz, 2H), 2.71 (t, J = 10.9 Hz, 1H), 2.30-2.13 (m, 4H), 2.08-1.87 (m, 2H), 1.76 (dtd, J = 22.3, 17.5, 10.4 Hz, 4H), 1.60-1.29 (m, 2H), 1.09 (dd, J = 8.4, 5.7 Hz, 2H), 0.83 (dd, J = 6.5, 4.7 Hz, 6H) ppm. 30 423.26 0.54 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.64 (d, J = 5.4 Hz, 1H), 7.35 (t, J = 12.8 Hz, 1H), 7.04 (d, J = 22.0 Hz, 1H), 6.83 (s, 2H), 6.45 (s, 1H), 4.72 (dq, J = 12.6, 6.4 Hz, 4H), 4.11 (d, J = 5.8 Hz, 3H), 3.60 (p, J = 6.4 Hz, 1H), 3.36-3.24 (m, 4H), 2.59-2.49 (m, 4H), 2.36 (s, 3H) ppm. 31 419.23 0.63 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.32-7.28 (m, 2H), 7.17 (s, 1H), 6.83 (s, 1H), 6.60 (s, 1H), 6.43 (s, 1H), 4.72 (p, J = 6.3 Hz, 3H), 3.64-3.54 (m, 1H), 3.37-3.26 (m, 3H), 2.63 (q, J = 7.6 Hz, 2H), 2.57-2.50 (m, 3H), 2.43 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H) ppm. 32 443.24 0.63 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.59-7.47 (m, 1H), 7.36 (dt, J = 9.3, 2.1 Hz, 1H), 7.16 (s, 1H), 7.13-7.02 (m, 1H), 6.77 (s, 1H), 6.63 (s, 1H), 6.43 (s, 1H), 4.80-4.64 (m, 4H), 3.68-3.51 (m, 1H), 3.38-3.24 (m, 4H), 2.62-2.49 (m, 4H), 2.35 (s, 3H) ppm. 33 427.36 0.65 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.28-7.21 (m, 2H), 7.12 (t, J = 1.9 Hz, 1H), 6.88-6.68 (m, 3H), 6.46 (d, J = 14.4 Hz, 1H), 4.81-4.70 (m, 4H), 3.67-3.48 (m, 1H), 3.33 (dd, J = 13.0, 8.2 Hz, 4H), 2.61-2.51 (m, 4H), 2.35 (s, 3H) ppm. 34 439 0.68 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.26 (d, J = 2.1 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 6.80 (s, 1H), 6.78-6.73 (m, 1H), 6.59 (s, 1H), 6.54 (s, 1H), 6.02 (s, 1H), 4.69 (t, J = 6.7 Hz, 1H), 4.63 (t, J = 6.5 Hz, 1H), 4.57 (s, 1H), 4.50 (d, J = 5.8 Hz, 1H), 4.32 (s, 1H), 4.05-3.95 (m, 1H), 3.60 (s, 1H), 3.45 (d, J = 9.2 Hz, 1H), 3.12 (d, J = 9.1 Hz, 1H), 3.06 (s, 1H), 2.95 (d, J = 9.2 Hz, 1H), 2.30 (s, 2H), 1.97 (d, J = 8.6 Hz, 1H) ppm. 35 396.23 0.62 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.23 (s, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.43 (s, 1H), 7.41 (s, 1H), 7.27 (t, J = 9.3 Hz, 1H), 6.65 (s, 1H), 4.25 (s, 2H), 3.81 (t, J = 5.0 Hz, 2H), 2.46 (s, 2H), 2.03 (s, 1H), 1.00-0.76 (m, 4H) ppm. 36 380.25 0.73 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.13 (s, 1H), 7.73 (dd, J = 10.1, 1.9 Hz, 2H), 7.59 (dd, J = 12.6, 6.0 Hz, 2H), 7.25-7.14 (m, 3H), 6.64 (s, 1H), 4.59 (t, J = 6.6 Hz, 2H), 4.45-4.40 (m, 2H), 3.81-3.53 (m, 4H), 3.20 (t, J = 6.0 Hz, 2H), 2.27 (s, 3H) ppm. 37 385.05 0.77 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.40 (s, 1H), 9.17 (s, 1H), 7.68-7.52 (m, 2H), 7.25 (t, J = 9.2 Hz, 1H), 7.16 (s, 1H), 3.53-3.39 (m, 2H), 6.95 (s, 1H), 6.39 (s, 1H), 3.74 (d, J = 11.5 Hz, 2H), 3.13 (p, J = 11.5 Hz, 4H), 2.82 (d, J = 4.6 Hz, 3H), 2.25 (s, 3H) ppm. 38 441.45 0.59 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.13 (s, 1H), 7.62 (dd, J = 8.5, 2.2 Hz, 2H), 7.29-7.16 (m, 1H), 7.05 (s, 1H), 6.38 (s, 1H), 5.96 (s, 1H), 5.33 (d, J = 7.7 Hz, 1H), 4.52 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 3.51-3.34 (m, 1H), 3.20 (s, 1H), 2.70 (t, J = 12.7 Hz, 2H), 2.12 (s, 3H), 1.98 (d, J = 10.9 Hz, 2H), 1.89 (t, J = 11.3 Hz, 2H), 1.41 (dd, J = 20.3, 11.2 Hz, 2H) ppm. 39 320 0.73 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.10 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.40-7.26 (m, 1H), 6.67 (s, 1H), 3.58 (d, J = 8.1 Hz, 1H), 3.50-3.30 (m, 1H), 3.24 (s, 1H), 3.03 (d, J = 11.4 Hz, 1H), 2.31 (d, J = 22.3 Hz, 1H), 2.29 (s, 3H), 2.02-1.78 (m, 1H) ppm. 40 410.28 0.59 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J = 6.7 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.52-7.44 (m, 1H), 7.27 (d, J = 1.5 Hz, 1H), 7.08 (s, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.46 (s, 1H), 4.80-4.65 (m, 4H), 3.68-3.54 (m, 1H), 3.38-3.25 (m, 4H), 2.63-2.50 (m, 4H), 2.37 (s, 3H) ppm. 41 536.32 0.67 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.23 (s, 1H), 6.75 (d, J = 12.9 Hz, 2H), 6.66 (dd, J = 7.2, 2.0 Hz, 2H), 6.40 (s, 1H), 6.33 (d, J = 12.0 Hz, 1H), 4.79-4.64 (m, 4H), 3.92 (s, 1H), 3.65-3.41 (m, 6H), 3.31 (dd, J = 9.6, 5.7 Hz, 5H), 3.21 (d, J = 7.1 Hz, 1H), 2.58-2.49 (m, 4H), 2.34 (s, 3H), 2.16-1.97 (m, 5H), 1.22 (t, J = 7.0 Hz, 3H) ppm. 42 354.79 0.69 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84-7.70 (m, 1H), 7.65 (dd, J = 5.6, 1.9 Hz, 1H), 7.34 (s, 1H), 7.06 (s, 1H), 6.52 (s, 1H), 3.61 (t, J = 6.7 Hz, 2H), 3.06 (s, 1H), 3.00 (d, J = 2.9 Hz, 1H), 2.40 (s, 3H), 2.28-2.11 (m, 4H) ppm. 43 372.08 2.38 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.08 (s, 1H), 8.16-7.90 (m, 1H), 7.85-7.58 (m, 1H), 7.40 (s, 1H), 7.04 (s, 1H), 6.56 (s, 1H), 3.85 (s, 1H), 3.23 (s, 1H), 2.27 (s, 1H) ppm. 44 375.25 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.10 (s, 1H), 7.83 (dd, J = 8.6, 1.1 Hz, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 6.91 (s, 1H), 6.77 (d, J = 1.4 Hz, 1H), 4.16 (d, J = 13.1 Hz, 2H), 2.72 (t, J = 11.7 Hz, 2H), 1.82 (td, J = 7.9, 3.9 Hz, 1H), 1.64 (d, J = 12.5 Hz, 2H), 1.56 (s, 1H), 1.19-0.97 (m, 2H), 0.91 (d, J = 6.4 Hz, 3H), 0.87-0.69 (m, 4H) ppm. 45 336 2.28 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.78-7.61 (m, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.14 (s, 1H), 6.81 (s, 1H), 6.66 (s, 1H), 6.39 (s, 1H), 3.89 (d, J = 4.1 Hz, 4H), 3.30-3.13 (m, 4H), 2.33 (s, 3H) ppm. 46 428.44 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.06 (s, 1H), 8.12-7.89 (m, 1H), 7.81-7.52 (m, 2H), 7.11 (s, 1H), 6.95 (s, 1H), 6.24 (s, 1H), 4.87 (s, 1H), 4.59 (t, J = 5.9 Hz, 2H), 4.48 (dd, J = 9.6, 5.6 Hz, 2H), 3.73 (s, 1H), 2.94 (s, 1H), 2.73 (s, 2H), 2.53 (s, 1H), 2.41-2.13 (m, 4H), 1.90 (s, 1H) ppm. 47 417.32 0.61 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.00 (t, J = 2.0 Hz, 1H), 6.65 (s, 1H), 6.55 (s, 1H), 6.25 (s, 1H), 4.68-4.54 (m, 4H), 3.49 (p, J = 6.4 Hz, 1H), 3.25-3.13 (m, 4H), 2.52-2.38 (m, 4H), 1.85-1.71 (m, 1H), 0.90-0.79 (m, 2H), 0.70-0.59 (m, 2H) ppm. 48 407.53 0.6 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J = 1.3 Hz, 1H), 8.83 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.31 (dd, J = 2.5, 1.5 Hz, 1H), 7.10 (t, J = 2.0 Hz, 1H), 6.75 (d, J = 5.0 Hz, 2H), 6.39 (s, 1H), 4.63 (dd, J = 6.4, 2.2 Hz, 4H), 3.59-3.43 (m, 1H), 3.31-3.18 (m, 4H), 2.56 (q, J = 7.6 Hz, 2H), 2.48 (dd, J = 14.3, 9.3 Hz, 4H), 1.20 (t, J = 7.6 Hz, 3H) ppm. 49 358.08 2.93 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.81 (s, 1H), 7.86 (d, J = 6.9 Hz, 1H), 7.63-7.27 (m, 4H), 7.02 (d, J = 12.4 Hz, 2H), 3.75 (s, 4H), 3.12 (s, 4H) ppm. 50 425.2 0.54 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 3.7 Hz, 1H), 7.37 (t, J = 2.1 Hz, 1H), 6.84 (s, 1H), 6.74 (s, 1H), 6.46 (s, 1H), 4.73 (p, J = 6.4 Hz, 4H), 3.60 (p, J = 6.4 Hz, 1H), 3.40-3.24 (m, 4H), 2.63 (q, J = 7.6 Hz, 2H), 2.58-2.46 (m, 4H), 1.27 (t, J = 7.6 Hz, 3H) ppm. 51 544.41 0.73 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 8.06-7.98 (m, 2H), 7.75-7.59 (m, 5H), 7.57-7.48 (m, 2H), 7.40-7.33 (m, 1H), 7.24 (d, J = 5.9 Hz, 2H), 6.67 (s, 2H), 4.84 (dd, J = 71.0, 21.8 Hz, 4H), 4.25-4.05 (m, 1H), 3.73 (s, 2H), 2.95 (s, 2H), 2.54 (s, 2H), 2.38 (s, 3H), 1.88 (s, 2H), 1.63 (d, J = 19.5 Hz, 2H) ppm. 52 428.4 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.06 (s, 1H), 8.11-7.84 (m, 1H), 7.78-7.55 (m, 2H), 7.11 (s, 1H), 6.94 (s, 1H), 6.23 (s, 1H), 4.85 (s, 1H), 4.58 (dd, J = 6.5, 5.1 Hz, 2H), 4.47 (dd, J = 10.6, 5.7 Hz, 2H), 3.66 (s, 1H), 3.31 (s, 1H), 2.89 (s, 1H), 2.69 (s, 2H), 2.38-2.17 (m, 4H), 1.86 (s, 1H) ppm. 53 415.28 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.16 (s, 1H), 7.61 (dd, J = 8.6, 2.1 Hz, 2H), 7.24 (m, 2H), 6.81 (s, 1H), 6.30 (s, 1H), 4.57 (m, 1H), 4.11 (dd, J = 10.5, 5.2 Hz, 1H), 3.67 (d, J = 10.6 Hz, 2H), 3.48 (d, J = 10.5 Hz, 1H), 3.41-3.35 (m, 1H), 3.17 (d, J = 5.3 Hz, 1H), 2.76 (m, 2H), 2.24 (m, 6H) ppm. 54 406.53 0.67 1H NMR (300 MHz, CDCl3) δ 8.93 (s, 1H), 8.28 (d, J = 5.0 Hz, 1H), 7.64 (s, 1H), 7.14 (s, 1H), 7.07 (d, J = 5.0 Hz, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 6.43 (s, 1H), 4.84-4.60 (m, 4H), 3.72-3.51 (m, 1H), 3.42-3.26 (m, 4H), 2.64-2.50 (m, 4H), 2.47 (s, 3H), 2.36 (s, 3H) ppm. 55 451.25 0.64 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.60-7.50 (m, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.38-7.30 (m, 1H), 7.14 (s, 1H), 6.70 (s, 1H), 6.61 (s, 1H), 6.35 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 3.65-3.53 (m, 1H), 3.38-3.24 (m, 4H), 2.60-2.48 (m, 4H), 1.90 (ddd, J = 13.5, 8.5, 5.1 Hz, 1H), 1.01-0.88 (m, 2H), 0.82-0.64 (m, 2H) ppm. 56 439.28 0.61 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.11 (s, 1H), 7.36-7.12 (m, 3H), 6.81 (dt, J = 11.2, 2.3 Hz, 2H), 6.31 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.53-3.38 (m, 1H), 3.25-3.05 (m, 4H), 2.46-2.34 (m, 3H), 2.22 (s, 3H) ppm. 57 422.41 2.48 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.88 (d, J = 7.7 Hz, 2H), 7.63-7.55 (m, 2H), 7.46 (t, J = 7.4 Hz, 2H), 6.89 (s, 1H), 4.36 (t, J = 18.6 Hz, 1H), 4.14 (d, J = 13.0 Hz, 1H), 3.52-3.25 (m, 5H), 2.52 (s, 3H), 1.91 (dd, J = 13.5, 6.7 Hz, 1H), 1.78 (s, 1H), 1.20 (s, 1H), 1.12 (s, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.8 Hz, 1H), 0.77 (d, J = 6.8 Hz, 2H) ppm. mixture of diastereomers 58 421.28 0.54 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.90 (d, J = 0.9 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.07 (t, J = 2.0 Hz, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 4.72 (dt, J = 16.1, 6.4 Hz, 4H), 3.60 (p, J = 6.4 Hz, 1H), 3.37-3.28 (m, 4H), 2.66 (dd, J = 13.3, 5.6 Hz, 2H), 2.64 (s, 3H), 2.59-2.50 (m, 4H), 1.29 (t, J = 7.6 Hz, 3H) ppm. 59 365 0.58 60 348 0.61 1H NMR (400 MHz, Acetone-d6) δ 8.79 (s, 1H), 8.25 (s, 1H), 7.93-7.82 (m, 2H), 7.59-7.49 (m, 3H), 7.40 (s, 1H), 7.38-7.30 (m, 1H), 6.64 (s, 1H), 2.95-2.65 (m, 5H), 2.31 (s, 3H), 2.23 (s, 3H), 1.97 (t, J = 10.9 Hz, 1H), 1.89 (td, J = 11.4, 3.1 Hz, 2H), 1.79-1.61 (m, 2H), 1.44 (ddd, J = 24.6, 12.3, 4.4 Hz, 1H) ppm. 61 424.19 0.76 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.44 (s, 1H), 7.32-7.13 (m, 3H), 6.90 (d, J = 20.4 Hz, 2H), 6.80 (ddd, J = 8.7, 6.6, 2.2 Hz, 1H), 6.20 (s, 1H), 4.75 (d, J = 6.5 Hz, 3H), 3.84-3.32 (m, 1H), 3.13 (dd, J = 12.6, 6.8 Hz, 2H), 2.63 (d, J = 2.8 Hz, 4H), 2.39 (s, 3H) ppm. 62 371.29 0.64 1H NMR (300 MHz, CD3OD) δ 8.80 (s, 1H), 7.85-7.75 (m, 2H), 7.51 (dd, J = 16.5, 8.1 Hz, 3H), 7.36 (dd, J = 13.5, 6.0 Hz, 2H), 6.68 (dd, J = 64.3, 48.6 Hz, 2H), 3.39 (dd, J = 6.5, 3.7 Hz, 4H), 3.26 (dd, J = 6.5, 3.6 Hz, 4H) ppm. 63 439.34 3.24 1H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.66-7.55 (m, 2H), 7.53 (s, 1H), 7.49 (s, 1H), 7.28 (td, J = 9.2, 2.2 Hz, 1H), 6.87 (s, 1H), 3.90 (m, 2H), 3.53 (m, 2H), 3.21 (m, 4H), 2.85 (s, 3H) ppm. 64 439.15 0.58 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.61 (dd, J = 20.2, 5.4 Hz, 1H), 7.37 (d, J = 5.4 Hz, 1H), 7.06 (s, 1H), 6.84 (s, 2H), 6.45 (s, 1H), 4.72 (dq, J = 12.6, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.24 (m, 4H), 2.62 (s, 3H), 2.54 (dd, J = 11.2, 6.3 Hz, 4H), 2.36 (s, 3H) ppm. 65 362.24 0.57 1H NMR (300 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.07 (s, 1H), 7.89-7.82 (m, 2H), 7.62 (s, 1H), 7.55 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 6.63 (s, 1H), 4.59 (t, J = 6.6 Hz, 2H), 4.46-4.40 (m, 2H), 3.82-3.71 (m, 1H), 3.70-3.52 (m, 3H), 3.24-3.14 (m, 2H), 2.27 (s, 3H) ppm. 66 452.29 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.33 (dd, J = 11.3, 5.7 Hz, 1H), 7.96 (dd, J = 10.0, 6.1 Hz, 1H), 7.14 (s, 1H), 6.88 (s, 1H), 6.34 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.50-3.39 (m, 1H), 3.21-3.10 (m, 4H), 2.45-2.36 (m, 4H), 2.23 (s, 3H) ppm. 67 441 0.64 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.19 (s, 1H), 7.63 (dd, J = 8.4, 2.1 Hz, 2H), 7.37 (d, J = 12.2 Hz, 2H), 7.27 (dd, J = 10.3, 8.1 Hz, 1H), 6.66 (s, 1H), 4.60 (t, J = 6.6 Hz, 2H), 4.51 (t, J = 6.1 Hz, 2H), 3.73-3.52 (m, 3H), 3.12 (s, 2H), 2.79-2.65 (m, 2H), 2.30 (s, 3H) ppm. 68 351.44 0.6 1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.20 (s, 1H), 9.05 (d, J = 1.3 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 2.6, 1.4 Hz, 1H), 7.16 (s, 1H), 6.92 (s, 1H), 6.33 (s, 1H), 3.20-3.00 (m, 4H), 2.46 (d, J = 4.8 Hz, 3H), 2.32-2.18 (m, 6H) ppm. 69 441.24 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, J = 13.3 Hz, 1H), 9.06 (s, 1H), 7.95 (dd, J = 12.9, 7.8 Hz, 1H), 7.68 (dd, J = 8.7, 5.1 Hz, 2H), 7.13 (s, 1H), 6.93 (s, 1H), 6.34 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.61-3.41 (m, 1H), 3.15 (s, 4H), 2.54 (d, J = 8.0 Hz, 2H), 2.34 (d, J = 43.4 Hz, 4H), 1.32-1.12 (m, 3H) ppm. 70 405.23 0.61 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.32-7.28 (m, 2H), 7.15 (s, 1H), 6.80 (s, 1H), 6.67 (s, 1H), 6.40 (s, 1H), 4.72 (p, J = 6.4 Hz, 4H), 3.58 (p, J = 6.5 Hz, 1H), 3.35-3.23 (m, 4H), 2.58-2.49 (m, 4H), 2.42 (s, 3H), 2.35 (d, J = 7.5 Hz, 3H) ppm. 71 390.46 0.65 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.76-7.66 (m, 2H), 7.57-7.47 (m, 2H), 7.42-7.32 (m, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 6.67 (d, J = 18.2 Hz, 2H), 4.70 (d, J = 6.6 Hz, 4H), 3.54 (p, J = 6.6 Hz, 1H), 2.90 (d, J = 9.9 Hz, 2H), 2.62-2.43 (m, 1H), 2.37 (s, 3H), 2.06-1.76 (m, 6H) ppm. 72 457.18 0.82 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.19 (s, 1H), 7.63 (d, J = 6.4 Hz, 2H), 7.26 (t, J = 9.5 Hz, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 6.40 (s, 1H), 4.34 (s, 2H), 4.26 (dd, J = 14.3, 7.2 Hz, 2H), 3.75 (s, 2H), 3.61 (s, 2H), 3.31 (s, 2H), 3.17 (s, 2H), 2.25 (s, 3H), 1.26 (dd, J = 13.9, 6.8 Hz, 3H) ppm. 73 449.35 0.85 H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.24 (d, J = 9.4 Hz, 1H), 7.10 (t, J = 2.0 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.72 (s, 1H), 6.61 (s, 1H), 6.35 (s, 1H), 4.79-4.60 (m, 4H), 3.59 (p, J = 6.3 Hz, 1H), 3.39-3.24 (m, 4H), 2.61-2.49 (m, 4H), 2.45 (s, 3H), 1.96-1.78 (m, 1H), 1.05-0.89 (m, 2H), 0.75 (dt, J = 6.7, 4.6 Hz, 2H) ppm. 74 392 0.6 1H NMR (400 MHz, CDCl3) δ 9.20 (d, J = 1.2 Hz, 1H), 8.91 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.49-8.30 (m, 1H), 7.31 (s, 1H), 7.22 (s, 1H), 6.82 (s, 1H), 6.70 (s, 1H), 4.76-4.56 (m, 4H), 3.59-3.45 (m, 1H), 2.94-2.76 (m, 3H), 2.37 (s, 3H), 2.01 (d, J = 12.5 Hz, 1H), 1.85 (dt, J = 38.3, 11.5 Hz, 3H), 1.55 (dd, J = 28.9, 16.5 Hz, 2H) ppm. 75 427.2 0.62 1H NMR (300 MHz, CDCl3) δ 9.19 (d, J = 1.3 Hz, 1H), 8.92 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.41 (dd, J = 2.5, 1.5 Hz, 1H), 7.19 (s, 1H), 6.77 (d, J = 8.0 Hz, 2H), 6.45 (s, 1H), 3.37-3.20 (m, 4H), 2.88-2.64 (m, 3H), 2.63-2.41 (m, 6H), 2.36 (s, 3H) ppm. 76 363 0.75 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.08 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.19 (s, 1H), 6.90 (s, 1H), 6.34 (s, 1H), 3.75 (s, 2H), 3.60-3.35 (m, 3H), 2.90 (s, 3H), 2.24 (s, 3H) ppm. 77 371 0.64 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.26 (s, 2H), 9.19 (s, 1H), 7.63 (dd, J = 8.5, 2.1 Hz, 2H), 7.26 (d, J = 2.3 Hz, 1H), 7.19 (s, 1H), 6.97 (s, 1H), 6.40 (s, 1H), 3.46-3.31 (m, 4H), 3.24 (s, 4H), 2.25 (s, 3H) ppm. 78 423 0.64 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.23 (d, J = 5.9 Hz, 2H), 6.80 (d, J = 7.6 Hz, 1H), 6.76 (t, J = 8.7 Hz, 1H), 6.63 (s, 1H), 6.54 (s, 1H), 6.06 (s, 1H), 4.25 (s, 1H), 3.65 (s, 1H), 3.48 (q, J = 8.8 Hz, 2H), 3.13 (d, J = 9.4 Hz, 1H), 2.90 (d, J = 9.7 Hz, 1H), 2.31 (s, 3H), 1.94 (t, J = 10.3 Hz, 3H), 1.27 (s, 1H), 0.55-0.30 (m, 4H) ppm. 79 445.41 0.64 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.10 (s, 1H), 6.88-6.73 (m, 2H), 6.65 (s, 1H), 6.43 (s, 1H), 3.77 (dd, J = 9.4, 8.4 Hz, 4H), 3.35-3.23 (m, 4H), 3.05-2.88 (m, 4H), 2.84 (dd, J = 12.3, 6.3 Hz, 1H), 2.35 (s, 3H) ppm. 80 340 0.36 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.09 (s, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.03 (s, 1H), 7.00 (s, 2H), 6.29 (d, J = 12.4 Hz, 1H), 3.90-3.60 (m, 4H), 3.20-2.96 (m, 4H) ppm. 81 374 0.58 1H NMR (300 MHz, Acetone-d6) δ 8.76 (s, 1H), 8.15-7.87 (m, 3H), 7.64 (s, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 6.53 (s, 1H), 3.42-3.20 (m, 3H), 2.75-2.55 (m, 3H), 2.42 (s, 3H), 2.40 (s, 3H) ppm. 82 463.36 0.69 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.72 (s, 1H), 7.46 (s, 1H), 7.40 (dd, J = 8.1, 2.2 Hz, 2H), 7.24 (s, 1H), 6.78 (ddt, J = 110.8, 76.2, 29.5 Hz, 3H), 4.75 (dt, J = 12.5, 6.5 Hz, 4H), 3.65 (s, 1H), 3.36 (s, 4H), 2.61 (s, 4H) ppm. 83 342.09 3.33 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 7.84 (td, J = 7.8, 2.1 Hz, 1H), 7.63-7.35 (m, 3H), 6.76 (d, J = 11.8 Hz, 1H), 6.67 (s, 1H), 5.86 (d, J = 12.1 Hz, 1H), 3.21 (t, J = 6.4 Hz, 4H), 1.95 (t, J = 6.5 Hz, 4H) ppm. 84 337.11 0.51 1H NMR (400 MHz, CD3OD) δ 9.38 (s, 1H), 8.90 (d, J = 6.9 Hz, 2H), 8.63 (d, J = 6.0 Hz, 2H), 8.15 (d, J = 26.7 Hz, 1H), 7.36 (d, J = 22.6 Hz, 1H), 7.12 (d, J = 24.4 Hz, 1H), 4.19 (s, 4H), 3.73 (s, 4H), 2.45 (s, 3H) ppm. 85 391.27 0.78 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.38 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.85-7.76 (m, 1H), 7.61 (s, 1H), 7.37 (d, J = 4.7 Hz, 2H), 6.94 (t, J = 56.1 Hz, 1H), 6.70 (s, 1H), 3.85-3.71 (m, 4H), 3.21-3.09 (m, 4H) ppm. 86 421.28 0.59 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.23 (dd, J = 8.0, 0.8 Hz, 1H), 7.18 (s, 1H), 6.95-6.84 (m, 1H), 6.78 (s, 1H), 6.70 (s, 1H), 6.40 (s, 1H), 4.71 (p, J = 6.1 Hz, 4H), 3.89 (s, 3H), 3.58 (p, J = 6.3 Hz, 1H), 3.36-3.26 (m, 4H), 2.58-2.47 (m, 4H), 2.34 (s, 3H) ppm. 87 403.42 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.04 (s, 1H), 7.82 (dd, J = 8.6, 1.0 Hz, 2H), 7.55 (dd, J = 10.7, 5.2 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 6.88 (s, 1H), 6.27 (s, 1H), 3.20-3.01 (m, 4H), 2.54 (dd, J = 9.5, 4.7 Hz, 4H), 2.44 (d, J = 8.1 Hz, 1H), 2.22 (s, 3H), 1.90-1.75 (m, 2H), 1.72-1.45 (m, 4H), 1.36 (dt, J = 16.2, 7.3 Hz, 2H) ppm. 88 399.29 0.62 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.14 (d, J = 22.9 Hz, 1H), 7.98 (ddd, J = 11.7, 7.0, 2.3 Hz, 1H), 7.73-7.58 (m, 2H), 6.87 (t, J = 9.6 Hz, 1H), 6.82 (s, 1H), 3.75-3.63 (m, 4H), 3.39-3.32 (m, 4H), 1.87 (ddd, J = 12.8, 8.0, 4.8 Hz, 1H), 0.92-0.82 (m, 2H), 0.82-0.74 (m, 2H) ppm. 89 384.33 3.63 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.27 (s, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.60 (dd, J = 13.0, 5.7 Hz, 3H), 7.48 (t, J = 7.4 Hz, 1H), 7.00 (s, 1H), 6.66 (s, 1H), 4.03-3.92 (m, 4H), 3.41 (s, 4H), 2.39 (s, 3H) ppm. 90 412 0.81 1H NMR (300 MHz, Acetone-d6) δ 8.89 (s, 1H), 8.33 (s, 1H), 7.65-7.48 (m, 2H), 7.42 (d, J = 16.4 Hz, 2H), 6.94 (tt, J = 9.0, 2.3 Hz, 1H), 6.66 (s, 1H), 4.71 (d, J = 13.2 Hz, 1H), 4.12-3.96 (m, 1H), 3.22 (td, J = 13.6, 2.7 Hz, 1H), 2.77 (ddd, J = 12.2, 8.4, 3.5 Hz, 1H), 2.63 (dd, J = 12.8, 9.9 Hz, 1H), 2.33 (s, 3H), 2.10 (s, 3H), 2.00-1.82 (m, 2H), 1.81-1.49 (m, 2H) ppm. 91 421.28 0.53 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.75 (d, J = 5.5 Hz, 1H), 7.53 (t, J = 5.4 Hz, 1H), 7.09 (t, J = 2.0 Hz, 1H), 6.88 (s, 1H), 6.74 (s, 1H), 6.49 (s, 1H), 4.73 (dq, J = 12.6, 6.4 Hz, 4H), 3.69-3.53 (m, 1H), 3.37-3.24 (m, 3H), 2.76 (s, 3H), 2.72-2.58 (m, 2H), 2.59-2.48 (m, 3H), 1.29 (dd, J = 9.5, 5.7 Hz, 3H) ppm. 92 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 2H), 7.52 (s, 1H), 7.29-7.19 (m, 1H), 7.18 (s, 1H), 6.62 (s, 1H), 4.58 (td, J = 6.5, 1.9 Hz, 2H), 4.50 (td, J = 6.0, 1.2 Hz, 2H), 3.69-3.60 (m, 1H), 3.29-3.21 (m, 1H), 2.97 (t, J = 8.4 Hz, 1H), 2.73 (dd, J = 14.9, 7.8 Hz, 1H), 2.59 (td, J = 8.7, 5.6 Hz, 1H), 2.44-2.38 (m, 1H), 2.26 (s, 3H), 1.79 (dt, J = 13.8, 8.3 Hz, 1H) ppm. 93 385 0.6 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J = 7.5 Hz, 1H), 9.18 (s, 1H), 7.63 (d, J = 6.4 Hz, 2H), 7.36 (t, J = 10.2 Hz, 2H), 7.26 (t, J = 9.3 Hz, 1H), 6.63 (s, 1H), 3.98 (s, 2H), 3.56 (dd, J = 15.0, 4.8 Hz, 4H), 2.29 (s, 3H) ppm. 94 379.24 0.59 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.38 (t, J = 8.2 Hz, 1H), 7.29 (t, J = 2.2 Hz, 1H), 7.26-7.13 (m, 2H), 6.88 (ddd, J = 16.8, 8.4, 7.7 Hz, 1H), 6.78 (d, J = 10.8 Hz, 2H), 6.40 (s, 1H), 3.89 (s, 3H), 3.35-3.26 (m, 4H), 2.68-2.58 (m, 4H), 2.40 (s, 3H), 2.35 (d, J = 12.3 Hz, 3H) ppm. 95 443.11 0.63 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.25 (dd, J = 7.8, 2.1 Hz, 2H), 7.10 (s, 1H), 6.83-6.73 (m, 2H), 6.66 (s, 1H), 6.42 (s, 1H), 3.84-3.71 (m, 1H), 3.49 (t, J = 8.9 Hz, 2H), 3.33-3.21 (m, 4H), 3.07 (dd, J = 9.0, 7.7 Hz, 2H), 2.54 (dd, J = 14.9, 10.0 Hz, 4H), 2.35 (s, 3H) ppm. 96 405 0.59 1H NMR (300 MHz, Acetone-d6) δ 9.17 (s, 1H), 9.05 (d, J = 1.1 Hz, 1H), 8.97 (d, J = 5.5 Hz, 2H), 7.80 (dd, J = 5.5, 1.2 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H), 6.84 (s, 1H), 3.41-3.21 (m, 4H) note: water peak under the CH2s, 2.61-2.49 (m, 4H), 2.29 (s, 3H) ppm. 97 451.44 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.13 (s, 1H), 7.71 (dd, J = 5.0, 2.8 Hz, 1H), 7.68 (s, 1H), 7.60 (td, J = 8.4, 6.5 Hz, 1H), 7.26 (s, 1H), 7.23-7.13 (m, 1H), 7.10 (s, 1H), 6.50 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.56-3.38 (m, 1H), 3.25-3.09 (m, 4H), 2.47-2.30 (m, 4H), 1.26 (d, J = 9.4 Hz, 9H) ppm. 98 385 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.15 (s, 1H), 7.70 (dd, J = 8.3, 5.6 Hz, 2H), 7.60 (dd, J = 14.7, 8.3 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 6.98 (s, 1H), 6.66 (d, J = 11.4 Hz, 1H), 6.03 (d, J = 13.1 Hz, 1H), 3.51 (d, J = 4.2 Hz, 2H), 3.43 (t, J = 6.1 Hz, 2H), 3.34 (s, 3H), 2.64 (d, J = 4.6 Hz, 2H), 2.48-2.40 (m, 2H), 2.27 (s, 3H), 1.92 (d, J = 4.9 Hz, 2H) ppm. 99 360.09 3.41 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.09 (s, 1H), 8.07-7.92 (m, 1H), 7.76-7.57 (m, 2H), 6.76 (d, J = 11.8 Hz, 1H), 6.69 (s, 1H), 5.88 (d, J = 12.3 Hz, 1H), 3.22 (t, J = 6.3 Hz, 4H), 1.96 (t, J = 6.5 Hz, 4H) ppm. 100 393.12 1.08 1H NMR (300 MHz, CD3OD) δ 9.83 (s, 1H), 8.80 (ddd, J = 11.4, 6.9, 2.7 Hz, 1H), 8.64 (ddt, J = 8.2, 4.2, 2.1 Hz, 1H), 8.46 (dt, J = 10.1, 8.7 Hz, 1H), 7.93 (dd, J = 12.8, 1.5 Hz, 2H), 4.88-4.71 (m, 4H), 4.54-4.37 (m, 4H) ppm. 101 1H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.17 (s, 1H), 7.74 (s, 1H), 7.69-7.58 (m, 2H), 7.25 (m, 2H), 6.85 (s, 1H), 5.18 (s, 1H), 4.57 (dd, J = 9.9, 4.3 Hz, 2H), 4.51 (dd, J = 13.1, 6.0 Hz, 2H), 3.82-3.71 (m, 1H), 2.92-2.70 (m, 4H), 2.29 (s, 3H), 2.21-1.97 (m, 2H) ppm. 102 425.22 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 9.03 (s, 1H), 7.96-7.70 (m, 2H), 7.42 (dd, J = 12.1, 5.5 Hz, 2H), 6.94-6.75 (m, 2H), 6.04 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.71 (s, 3H), 3.44 (dt, J = 15.2, 7.7 Hz, 1H), 3.25-3.07 (m, 4H), 2.37 (t, J = 22.6 Hz, 4H) ppm. 103 506.25 0.69 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.20 (s, 1H), 6.77 (s, 1H), 6.70-6.54 (m, 3H), 6.40 (s, 1H), 6.20 (d, J = 12.1 Hz, 1H), 4.79-4.65 (m, 44H), 3.60 (dd, J = 13.0, 6.6 Hz, 2H), 3.52-3.40 (m, 1H), 3.36-3.29 (m, 4H), 3.28-3.14 (m, 1H), 2.53 (s, 4H), 2.36 (d, J = 11.7 Hz, 3H), 2.06-1.99 (m, 1H), 1.82-1.48 (m, 5H), 1.32-1.21 (m, 3H) ppm. 104 392.4 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 9.12 (s, 1H), 8.49 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.08 (ddd, J = 8.2, 7.5, 1.8 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.40 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 7.15 (s, 1H), 6.92 (s, 1H), 6.32 (s, 1H), 4.56 (q, J = 6.6 Hz, 3H), 4.54-4.36 (m, 3H), 3.55-3.38 (m, 1H), 3.16 (dd, J = 7.4, 3.7 Hz, 4H), 2.46-2.40 (m, 4H), 2.24 (s, 3H) ppm. 105 401.27 0.64 1H NMR (400 MHz, CDCl3) δ 8.34-8.25 (m, 1H), 7.26-7.12 (m, 3H), 6.83-6.72 (m, 1H), 6.54-6.45 (m, 2H), 5.45-5.20 (m, 1H), 3.83 (dd, J = 26.4, 13.0 Hz, 1H), 3.72-3.48 (m, 3H), 2.34 (dd, J = 22.0, 10.3 Hz, 1H), 2.22-1.98 (m, 1H), 1.92-1.80 (m, 1H), 1.03 (s, 2H), 0.84 (d, J = 3.0 Hz, 2H) ppm. 106 385.15 0.86 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 12.0 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.22 (dd, J = 7.7, 1.6 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J = 1.5 Hz, 1H), 6.94-6.91 (m, 1H), 6.68 (d, J = 1.5 Hz, 1H), 3.90 (s, 3H), 3.57 (s, 4H), 1.67 (s, 6H) ppm. 107 441.4 0.65 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.25 (dd, J = 7.9, 2.2 Hz, 2H), 7.14 (t, J = 2.1 Hz, 1H), 6.80 (ddd, J = 10.9, 3.3, 1.9 Hz, 3H), 6.46 (s, 1H), 4.79-4.65 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 2.58-2.45 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 108 370 0.62 1H NMR (400 MHz, Acetone-d6) δ 8.92 (s, 1H), 8.37 (s, 1H), 7.63-7.53 (m, 2H), 7.45 (s, 1H), 7.41 (s, 1H), 7.00 (tt, J = 9.1, 2.3 Hz, 1H), 6.65 (s, 1H), 3.11 (d, J = 11.9 Hz, 2H), 2.78-2.63 (m, 8H), 2.57 (tt, J = 11.9, 3.7 Hz, 1H), 2.32 (s, 3H), 1.82-1.73 (m, 2H), 1.63 (qd, J = 12.4, 4.0 Hz, 2H) ppm. 109 385 0.66 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 7.80-7.66 (m, 2H), 7.65-7.52 (m, 1H), 7.19 (t, J = 7.4 Hz, 1H), 6.82 (s, 1H), 6.68 (d, J = 11.8 Hz, 1H), 5.88 (d, J = 12.1 Hz, 1H), 3.46 (t, J = 8.1 Hz, 1H), 3.35 (d, J = 11.0 Hz, 4H), 3.30-3.15 (m, 1H), 3.05 (t, J = 8.5 Hz, 1H), 2.83-2.68 (m, 1H), 2.22 (s, 6H), 1.91-1.71 (m, 1H) ppm. 110 320 2.3 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.79-7.60 (m, 2H), 7.60-7.38 (m, 2H), 7.40-7.28 (m, 1H), 6.79 (s, 1H), 6.62 (s, 2H), 6.06 (s, 1H), 3.34 (m, 4H), 2.32 (s, 3H), 2.03 (m, 4H) ppm. 111 407.33 0.56 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.90 (d, J = 0.8 Hz, 1H), 7.59 (s, 1H), 7.03 (d, J = 11.4 Hz, 1H), 6.90 (s, 1H), 6.88 (s, 1H), 6.45 (s, 1H), 4.72 (dt, J = 16.0, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.25 (m, 4H), 2.64 (s, 3H), 2.59-2.49 (m, 4H), 2.37 (s, 3H) ppm. 112 431.25 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.18 (s, 1H), 7.67-7.55 (m, 2H), 7.31-7.20 (m, 1H), 7.02-6.92 (m, 2H), 6.31 (d, J = 12.7 Hz, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.51-3.39 (m, 1H), 3.23-3.14 (m, 4H), 2.44-2.34 (m, 4H) ppm. 113 427.45 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 9.05 (s, 1H), 8.09-7.95 (m, 1H), 7.70 (ddt, J = 19.2, 17.6, 5.8 Hz, 2H), 6.89 (s, 1H), 6.52 (s, 1H), 5.92 (s, 1H), 5.62 (d, J = 6.5 Hz, 1H), 4.56 (td, J = 6.5, 3.6 Hz, 2H), 4.45 (dd, J = 12.6, 6.1 Hz, 2H), 3.85 (s, 1H), 3.67-3.50 (m, 1H), 2.78 (dt, J = 17.5, 8.8 Hz, 1H), 2.60 (dd, J = 13.9, 8.1 Hz, 1H), 2.47-2.34 (m, 2H), 2.33-2.17 (m, 1H), 2.14 (s, 3H), 1.66 (td, J = 12.8, 7.4 Hz, 1H) ppm. 114 453.28 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.59 (m, 2H), 7.23 (m, 2H), 6.80 (s, 1H), 6.31 (s, 1H), 3.93 (m, 1H), 3.63 (d, J = 11.8 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H), 3.40 (t, J = 7.0 Hz, 2H), 2.83-2.72 (m, 1H), 2.63 (m, 1H), 2.26-2.18 (m, 5H), 1.93 (m, 2H), 1.71 (m, 4H) ppm. 115 391 0.62 116 386.19 0.72 117 376 0.8 1H NMR (400 MHz, Acetone-d6) δ 8.81 (d, J = 4.5 Hz, 1H), 8.35 (d, J = 3.8 Hz, 1H), 7.95-7.84 (m, 2H), 7.62-7.51 (m, 3H), 7.44 (s, 1H), 7.36 (td, J = 7.4, 3.1 Hz, 1H), 6.68 (d, J = 15.5 Hz, 1H), 4.78-4.50 (m, 1H), 4.01-3.86 (m, 1H), 3.19-3.05 (m, 1H), 2.70 (ddd, J = 11.6, 7.9, 4.0 Hz, 1H), 2.54 (dd, J = 14.8, 8.0 Hz, 2H), 2.32 (s, 3H), 1.91-1.71 (m, 3H), 1.71-1.42 (m, 2H) ppm. 118 391.36 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.05 (s, 1H), 7.82 (dd, J = 8.6, 1.0 Hz, 2H), 7.55 (dd, J = 10.8, 5.2 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.16 (s, 1H), 6.88 (s, 1H), 6.29 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.45 (p, J = 6.2 Hz, 1H), 3.23-3.03 (m, 4H), 2.45-2.35 (m, 4H), 2.22 (s, 3H) ppm. 119 399 0.63 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.25 (d, J = 4.5 Hz, 2H), 7.23 (d, J = 2.1 Hz, 1H), 7.19 (s, 1H), 6.77 (tt, J = 8.7, 2.2 Hz, 1H), 6.69 (s, 1H), 6.62 (s, 1H), 6.40 (s, 1H), 3.66-3.52 (m, 2H), 3.48 (dt, J = 11.9, 5.4 Hz, 1H), 3.14-2.91 (m, 2H), 2.68 (s, 1H), 2.51 (d, J = 11.5 Hz, 1H), 2.40 (s, 2H), 2.33 (s, 2H), 1.21 (dd, J = 9.1, 4.8 Hz, 3H) ppm. 120 374 0.64 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.79-7.60 (m, 2H), 7.58-7.43 (m, 2H), 7.42-7.28 (m, 1H), 7.17 (s, 1H), 6.68 (s, 1H), 6.62 (s, 1H), 3.17 (d, J = 11.5 Hz, 2H), 2.50 (tt, J = 11.7, 3.8 Hz, 1H), 2.40-2.22 (m, 5H), 2.04 (s, 1H), 1.94-1.55 (m, 6H), 0.47 (d, J = 6.8 Hz, 4H) ppm. 121 454.32 0.61 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.12 (d, J = 12.2 Hz, 2H), 7.11 (s, 2H), 7.00 (t, J = 1.8 Hz, 1H), 6.84 (s, 1H), 6.70 (d, J = 20.8 Hz, 1H), 6.39 (s, 1H), 4.80-4.60 (m, 4H), 3.69-3.47 (m, 1H), 3.29 (dd, J = 14.1, 9.1 Hz, 4H), 2.53 (dd, J = 12.9, 8.1 Hz, 4H), 1.96-1.84 (m, 1H), 1.07-0.89 (m, 2H), 0.84-0.65 (m, 2H) ppm. 122 397 0.59 1H NMR (300 MHz, Acetone-d6) δ 9.08 (s, 1H), 8.44 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.88-7.76 (m, 1H), 7.56-7.49 (m, 1H), 7.31 (t, J = 2.0 Hz, 1H), 6.97 (s, 1H), 6.41 (s, 1H), 3.78 (d, J = 12.4 Hz, 2H), 3.29 (s, 3H), 3.25 (d, J = 6.1 Hz, 2H), 2.83 (d, J = 9.2 Hz, 4H), 2.74 (td, J = 12.3, 2.4 Hz, 2H), 2.28 (s, 3H), 1.89-1.65 (m, 3H— methine proton contained within the multiplet), 1.49-1.25 (m, 2H) ppm. 123 483.2 0.67 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.62 (m, 3H), 7.43 (s, 1H), 7.28 (tt, J = 9.3, 2.3 Hz, 1H), 6.85 (s, 1H), 3.95-3.84 (m, 2H), 3.34 (d, J = 11.8 Hz, 1H), 3.24 (dd, J = 11.4, 2.7 Hz, 1H), 3.21-3.04 (m, 2H), 2.99-2.88 (m, 1H), 1.31 (s, 3H), 1.28 (s, 3H) ppm. 124 351.16 0.6 1H NMR (300 MHz, CD3OD) δ 9.17-9.02 (m, 2H), 8.58 (d, J = 2.6 Hz, 1H), 8.51 (dd, J = 2.6, 1.4 Hz, 1H), 7.32 (t, J = 2.1 Hz, 1H), 7.00 (s, 1H), 6.50 (s, 1H), 3.43 (dd, J = 12.3, 6.2 Hz, 8H), 2.63 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H) ppm. 125 429.14 0.78 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 2H), 9.19 (s, 1H), 7.63 (d, J = 6.9 Hz, 3H), 7.26 (t, J = 8.9 Hz, 1H), 7.18 (s, 1H), 6.95 (s, 1H), 6.40 (s, 1H), 4.24 (s, 2H), 3.76-3.57 (m, 4H), 3.48 (dd, J = 11.8, 4.4 Hz, 4H), 2.25 (s, 3H) ppm. 127 419.44 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.05 (s, 1H), 7.91-7.76 (m, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 5.7 Hz, 1H), 6.28 (s, 1H), 4.18-3.55 (m, 2H), 3.11 (d, J = 3.4 Hz, 4H), 2.75 (dd, J = 15.6, 6.5 Hz, 1H), 2.63-2.51 (m, 4H), 2.37 (q, J = 7.1 Hz, 1H), 2.25 (d, J = 15.2 Hz, 3H), 1.97 (ddt, J = 31.7, 21.1, 12.4 Hz, 2H), 1.17-0.94 (m, 3H) ppm. 128 411 0.63 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.16 (s, 1H), 7.60 (dd, J = 8.5, 2.0 Hz, 2H), 7.31 (s, 1H), 7.28-7.12 (m, 1H), 6.75 (s, 1H), 6.33 (s, 1H), 3.77 (d, J = 9.6 Hz, 1H), 3.61 (d, J = 11.6 Hz, 1H), 3.10-2.97 (m, 2H), 2.75 (td, J = 11.6, 3.1 Hz, 1H), 2.43 (t, J = 10.6 Hz, 1H), 2.29-2.16 (m, 3H), 2.14-1.98 (m, 2H), 1.93-1.76 (m, 1H), 1.77-1.60 (m, 2H), 1.39 (tt, J = 17.7, 8.7 Hz, 1H) ppm. 129 447.34 0.6 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.38 (s, 1H), 7.01 (t, J = 2.0 Hz, 1H), 6.89 (s, 1H), 6.80 (s, 1H), 6.38 (s, 1H), 4.71 (dt, J = 16.0, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.37-3.25 (m, 4H), 2.71 (s, 3H), 2.59 (s, 3H), 2.56-2.47 (m, 4H), 1.97-1.84 (m, 1H), 1.05-0.92 (m, 2H), 0.82-0.68 (m, 2H) ppm. 130 481.27 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.22 (s, 1H), 7.60 (dd, J = 8.5, 2.2 Hz, 2H), 7.50 (s, 1H), 7.42 (s, 1H), 7.27 (ddd, J = 11.5, 6.8, 2.2 Hz, 1H), 6.75 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.52-3.41 (m, 1H), 3.29-3.21 (m, 4H), 2.46-2.38 (m, 4H) ppm. 131 343.15 0.85 1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.17 (s, 1H), 7.69-7.55 (m, 3H), 7.24 (ddd, J = 9.4, 8.3, 3.6 Hz, 2H), 6.73 (s, 1H), 4.96 (dd, J = 8.3, 5.7 Hz, 2H), 4.65-4.57 (m, 2H), 4.25-4.11 (m, 1H), 2.30 (s, 3H) ppm. 132 453.15 0.6 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 4.0 Hz, 1H), 8.64 (t, J = 4.7 Hz, 1H), 7.36 (d, J = 5.4 Hz, 1H), 7.07 (t, J = 2.0 Hz, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 6.49 (s, 1H), 4.72 (dq, J = 12.6, 6.4 Hz, 4H), 3.60 (p, J = 6.4 Hz, 1H), 3.37-3.25 (m, 4H), 2.66 (dd, J = 12.9, 5.2 Hz, 2H), 2.63 (s, 3H), 2.60-2.47 (m, 4H), 1.29 (t, J = 7.6 Hz, 3H) ppm. 133 363 0.59 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.67 (d, J = 7.7 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.20 (s, 1H), 6.74 (s, 1H), 6.60 (s, 1H), 6.38 (s, 1H), 3.69-3.51 (m, 2H), 3.14-2.90 (m, 2H), 2.68 (d, J = 18.9 Hz, 1H), 2.60-2.26 (m, 7H), 1.21 (d, J = 5.6 Hz, 3H) ppm. 134 452.29 0.59 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.09 (s, 1H), 6.70 (s, 1H), 6.67 (s, 1H), 6.37 (s, 1H), 4.71 (p, J = 6.2 Hz, 4H), 3.73-3.48 (m, 1H), 3.40-3.16 (m, 4H), 2.64-2.45 (m, 4H), 2.01-1.75 (m, 1H), 1.04-0.87 (m, 2H), 0.85-0.63 (m, 2H) ppm. 135 357.11 1.06 1H NMR (300 MHz, CD3OD) δ 8.83 (s, 1H), 7.90-7.74 (m, 2H), 7.54 (dd, J = 8.7, 7.2 Hz, 2H), 7.47-7.32 (m, 1H), 6.96 (s, 2H), 3.91-3.71 (m, 4H), 3.57-3.43 (m, 4H) ppm. 136 407.52 0.58 1H NMR (300 MHz, CDCl3) δ 9.19 (d, J = 1.4 Hz, 1H), 8.93 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.40 (dd, J = 2.5, 1.5 Hz, 1H), 7.18 (s, 1H), 6.82 (d, J = 14.8 Hz, 2H), 6.44 (s, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.37-3.25 (m, 4H), 2.64-2.52 (m, 4H), 2.36 (s, 3H), 1.44 (s, 3H) ppm. 137 441.36 0.64 1H NMR (300 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.43 (s, 1H), 9.18 (s, 1H), 7.71-7.55 (m, 2H), 7.27 (ddd, J = 9.3, 5.7, 2.3 Hz, 1H), 7.11 (s, 1H), 6.99 (s, 1H), 6.39 (s, 1H), 4.15 (dd, J = 10.2, 4.2 Hz, 1H), 4.10-3.90 (m, 2H), 3.89-3.61 (m, 4H), 3.51 (dd, J = 22.4, 10.8 Hz, 2H), 3.34-3.01 (m, 4H), 2.37-2.14 (m, 5H) ppm. 138 350 0.56 1H NMR (400 MHz, Acetone-d6) δ 8.95 (s, 1H), 8.46 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.27 (s, 1H), 8.03 (ddd, J = 8.2, 7.5, 1.8 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.36 (ddd, J = 7.4, 4.8, 1.0 Hz, 1H), 7.31 (t, J = 1.9 Hz, 1H), 7.01 (s, 1H), 6.38 (s, 1H), 3.28-3.13 (m, 4H), 2.58-2.42 (m, 4H), 2.28 (s, 3H), 2.26 (s, 3H) ppm. 139 443 0.63 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.22 (d, J = 5.6 Hz, 2H), 7.16 (s, 1H), 7.12 (s, 1H), 6.88 (s, 1H), 6.78 (t, J = 8.7 Hz, 1H), 6.41 (s, 1H), 5.40-5.24 (m, 2H), 4.77 (t, J = 7.2 Hz, 2H), 4.53-4.43 (m, 1H), 3.90 (t, J = 11.5 Hz, 2H), 3.54 (d, J = 13.1 Hz, 2H), 3.30 (t, J = 9.7 Hz, 2H), 3.16 (d, J = 10.3 Hz, 2H), 2.34 (s, 3H) ppm. 140 434.28 0.63 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.27 (s, 1H), 8.14 (dd, J = 8.5, 7.4 Hz, 1H), 7.99 (dd, J = 11.0, 1.9 Hz, 1H), 7.85 (dd, J = 8.6, 1.9 Hz, 1H), 7.14 (s, 1H), 6.89 (s, 1H), 6.34 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.46 (m, 1H), 3.15 (m, 4H), 2.45-2.38 (m, 4H), 2.24 (s, 3H) ppm. 141 383.24 0.62 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.12 (s, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.2, 1.2 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.22 (s, 1H), 6.82 (s, 1H), 6.30 (s, 1H), 3.19-3.06 (m, 4H), 2.48-2.42 (m, 4H), 2.22 (d, J = 2.5 Hz, 6H) ppm. 142 359 0.62 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.67 (dd, J = 8.6, 1.1 Hz, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 6.63 (s, 1H), 6.38 (s, 1H), 3.61-3.42 (m, 2H), 3.25-3.05 (m, 2H), 2.91-2.70 (m, 1H), 2.32 (s, 3H), 2.17-1.91 (m, 4H) ppm. 143 392 0.9 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 6.73 (s, 1H), 6.66 (s, 1H), 4.25 (s, 2H), 3.71 (s, 3H), 2.78 (s, 2H), 2.66 (s, 1H), 2.36 (s, 3H), 2.07 (d, J = 11.6 Hz, 1H), 1.79 (d, J = 11.8 Hz, 1H), 1.72-1.53 (m, 3H) ppm. 144 413.37 0.77 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.73-7.65 (m, 2H), 7.59-7.49 (m, 2H), 7.44-7.36 (m, 2H), 7.16 (s, 1H), 6.93 (s, 1H), 6.63 (dd, J = 66.1, 47.2 Hz, 2H), 3.88-3.78 (m, 2H), 3.70-3.64 (m, 2H), 3.35-3.25 (m, 4H), 2.18 (s, 3H) ppm. 145 387.14 0.82 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.13 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 20.8, 14.6 Hz, 3H), 6.65 (s, 1H), 3.78 (s, 3H), 3.74-3.65 (m, 4H), 3.50-3.35 (m, 4H) ppm. 146 359 0.78 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.77-7.60 (m, 2H), 7.50 (dd, J = 11.2, 4.6 Hz, 2H), 7.41-7.29 (m, 1H), 6.73 (s, 1H), 6.70 (s, 1H), 6.37 (s, 1H), 3.69 (dd, J = 12.4, 3.4 Hz, 1H), 3.45 (dd, J = 9.7, 6.1 Hz, 1H), 3.26 (dd, J = 12.4, 8.7 Hz, 1H), 3.14-3.00 (m, 1H), 2.91 (ddd, J = 12.4, 8.6, 3.7 Hz, 1H), 2.32 (s, 3H), 2.15-2.01 (m, 1H), 1.96-1.68 (m, 3H) ppm. 147 325.19 0.81 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.14 (s, 1H), 7.77-7.69 (m, 2H), 7.60 (dt, J = 8.4, 5.6 Hz, 2H), 7.31 (s, 1H), 7.19 (td, J = 8.3, 1.5 Hz, 1H), 6.72 (s, 1H), 4.95 (dd, J = 8.4, 5.8 Hz, 2H), 4.62 (dd, J = 6.7, 5.8 Hz, 2H), 4.24-4.11 (m, 1H), 2.30 (s, 3H) ppm. 148 392 0.63 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 6.41 (s, 1H), 3.72 (d, J = 12.6 Hz, 2H), 3.47 (dd, J = 11.0, 4.7 Hz, 2H), 3.35 (s, 3H), 2.75 (t, J = 11.4 Hz, 2H), 2.32 (s, 3H), 1.80 (d, J = 13.0 Hz, 2H), 1.58 (s, 3H), 1.40 (d, J = 7.9 Hz, 2H) ppm. 149 375 0.61 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 9.04 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.15 (s, 1H), 6.87 (s, 1H), 6.28 (s, 1H), 3.14-3.01 (m, 4H), 2.80-2.59 (m, 4H), 2.22 (s, 3H), 1.72-1.58 (m, 1H), 0.43 (dd, J = 6.1, 4.0 Hz, 2H), 0.36 (d, J = 3.1 Hz, 2H) ppm. 150 398.26 0.61 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.65-7.53 (m, 1H), 7.49-7.30 (m, 2H), 7.15 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.84 (s, 1H), 4.10 (d, J = 10.7 Hz, 2H), 3.64-3.50 (m, 2H), 2.94-2.79 (m, 1H), 2.08-1.97 (m, 1H), 1.97-1.78 (m, 4H), 1.09-1.00 (m, 2H), 0.96 (ddd, J = 18.9, 10.7, 8.2 Hz, 2H) ppm. 151 384 0.63 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.25-7.20 (m, 2H), 7.16 (s, 1H), 6.78 (tt, J = 8.7, 2.2 Hz, 1H), 6.70 (s, 1H), 6.66 (s, 1H), 3.05 (d, J = 11.2 Hz, 2H), 2.47 (d, J = 15.7 Hz, 1H), 2.38 (s, 3H), 2.36 (s, 3H), 2.16 (s, 2H), 1.90 (s, 4H) ppm. 152 431 0.66 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.06 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.24 (s, 1H), 6.71 (s, 1H), 6.21 (s, 1H), 3.96-3.85 (m, 1H), 3.51 (dd, J = 11.5, 2.8 Hz, 1H), 3.00 (dd, J = 18.9, 9.7 Hz, 2H), 2.70 (t, J = 10.9 Hz, 1H), 2.34-2.14 (m, 4H), 2.10-1.88 (m, 2H), 1.87-1.59 (m, 4H), 1.46 (ddt, J = 21.4, 14.9, 5.5 Hz, 2H), 1.18-1.05 (m, 1H), 0.83 (dd, J = 6.5, 4.2 Hz, 6H) ppm. 153 430.33 0.64 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.59 (s, 1H), 7.91 (d, J = 5.7 Hz, 1H), 7.33 (d, J = 5.7 Hz, 1H), 7.07 (d, J = 14.0 Hz, 2H), 6.91 (s, 1H), 6.28 (dd, J = 67.1, 46.2 Hz, 2H), 2.94-2.87 (m, 4H), 2.56-2.39 (m, 4H), 1.44-1.32 (m, 1H), 0.26-0.06 (m, 4H) ppm. 154 410.44 0.65 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 7.98 (q, J = 7.9 Hz, 1H), 7.68 (dd, J = 7.8, 1.1 Hz, 1H), 7.10 (s, 1H), 6.92-6.82 (m, 2H), 6.74 (s, 1H), 6.44 (s, 1H), 4.74 (d, J = 6.4 Hz, 4H), 3.73-3.56 (m, 1H), 3.34 (s, 4H), 2.59 (s, 4H), 2.36 (s, 3H) ppm. 155 353.47 0.67 1H NMR (400 MHz, DMSO-d6) δ 9.62 (d, J = 12.8 Hz, 1H), 9.23 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 7.09 (s, 1H), 6.87 (dd, J = 7.2, 2.2 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 6.64 (s, 1H), 3.87 (s, 3H), 3.26 (s, 3H) ppm. 156 350.22 0.5 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.11 (s, 1H), 7.83 (dd, J = 8.6, 1.1 Hz, 2H), 7.56 (dd, J = 10.7, 5.2 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 6.96 (s, 1H), 6.72 (s, 1H), 3.49-3.35 (m, 4H), 2.46-2.31 (m, 4H), 2.24 (s, 3H), 2.22 (s, 3H) ppm. 157 375 0.6 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.06 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.26 (s, 1H), 6.82 (s, 1H), 6.30 (s, 1H), 3.75 (d, J = 9.8 Hz, 1H), 3.60 (d, J = 11.7 Hz, 1H), 3.34 (s, 1H), 3.12-2.93 (m, 2H), 2.75 (td, J = 11.6, 3.1 Hz, 1H), 2.42 (t, J = 10.6 Hz, 1H), 2.24 (d, J = 15.1 Hz, 4H), 2.07 (dd, J = 17.1, 8.3 Hz, 2H), 1.96-1.78 (m, 1H), 1.78-1.60 (m, 2H), 1.39 (tt, J = 17.7, 8.8 Hz, 1H) ppm. 158 358.15 2.9 1H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 42.0 Hz, 1H), 9.08 (s, 1H), 7.88 (dd, J = 8.9, 4.6 Hz, 2H), 7.42 (t, J = 8.7 Hz, 2H), 7.06 (d, J = 10.5 Hz, 2H), 6.32 (t, J = 42.3 Hz, 1H), 3.74 (d, J = 29.6 Hz, 4H), 3.15 (s, 4H) ppm. 159 335 0.58 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 9.08 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 6.39 (s, 1H), 3.48-3.30 (m, 4H), 3.25 (s, 4H), 2.25 (s, 3H) ppm. 160 374.24 0.59 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.09 (s, 1H), 7.88-7.81 (m, 2H), 7.66 (s, 1H), 7.55 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.29 (s, 1H), 6.80 (s, 1H), 6.23 (s, 1H), 4.66 (t, J = 6.5 Hz, 2H), 4.56 (t, J = 5.9 Hz, 2H), 4.05-3.93 (m, 1H), 3.85 (s, 2H), 3.63 (s, 2H), 2.28 (s, 3H) ppm. 161 453.28 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.16 (s, 1H), 7.66-7.52 (m, 2H), 7.31-7.17 (m, 2H), 6.81 (s, 1H), 6.33 (s, 1H), 3.91 (m, 1H), 3.76 (d, J = 12.0 Hz, 2H), 3.29 (m, 2H), 2.77 (t, J = 11.5 Hz, 2H), 2.27-2.18 (m, 5H), 1.91 (m, 2H), 1.80-1.73 (m, 2H), 1.61 (d, J = 9.6 Hz, 2H) ppm. 162 414 0.63 1H NMR (400 MHz, Acetone-d6) δ 8.91 (s, 1H), 8.28 (s, 1H), 7.56 (dd, J = 8.6, 2.2 Hz, 2H), 7.32 (t, J = 1.9 Hz, 1H), 7.00 (ddd, J = 9.1, 5.7, 2.3 Hz, 1H), 6.93 (s, 1H), 6.39 (s, 1H), 3.78 (d, J = 12.4 Hz, 2H), 3.29 (s, 3H), 3.25 (d, J = 6.2 Hz, 2H), 2.77-2.67 (m, 2H), 2.27 (s, 3H), 1.80 (d, J = 13.1 Hz, 2H), 1.74 (dd, J = 10.7, 4.4 Hz, 1H), 1.38 (ddd, J = 15.4, 12.4, 3.9 Hz, 2H) ppm. 163 444.42 0.55 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.22 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 7.09-6.66 (m, 5H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.48 (dd, J = 12.5, 6.3 Hz, 1H), 3.25-3.17 (m, 4H), 2.46-2.38 (m, 4H) ppm. 164 386.28 0.85 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.15 (s, 1H), 7.68-7.53 (m, 2H), 7.32-7.16 (m, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 5.93 (s, 1H), 4.08 (d, J = 2.5 Hz, 1H), 3.44 (dd, J = 10.4, 5.0 Hz, 1H), 3.32-3.18 (m, 6H), 2.21 (s, 3H), 2.08 (m, 2H) ppm. 165 392.31 0.67 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.65-7.55 (m, 2H), 7.42 (t, J = 7.9 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 2.1 Hz, 1H), 6.87 (s, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 4.15-3.96 (m, 2H), 3.91-3.83 (m, 1H), 3.82-3.77 (m, 4H), 3.72 (dd, J = 8.4, 7.3 Hz, 1H), 3.32 (dd, J = 15.4, 7.7 Hz, 1H), 3.19-3.09 (m, 4H), 2.36-2.24 (m, 1H), 1.98 (ddd, J = 15.9, 12.3, 7.9 Hz, 1H) ppm. 166 372 0.87 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.14 (s, 1H), 7.81-7.65 (m, 2H), 7.65-7.49 (m, 1H), 7.20 (t, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.70 (d, J = 11.4 Hz, 1H), 6.11 (d, J = 12.9 Hz, 1H), 3.74 (t, J = 4.6 Hz, 2H), 3.57 (dd, J = 11.2, 5.7 Hz, 6H), 2.01-1.84 (m, 2H) ppm. 167 342.13 3.36 1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J = 29.2 Hz, 1H), 9.09 (d, J = 45.6 Hz, 1H), 7.71 (t, J = 8.1 Hz, 2H), 7.56 (d, J = 22.2 Hz, 1H), 6.85-6.58 (m, 2H), 5.83 (t, J = 29.4 Hz, 1H), 3.10 (d, J = 104.7 Hz, 4H), 1.96 (s, 4H) ppm. 168 400.23 0.89 1H NMR (300 MHz, CD3OD) δ 8.53 (s, 1H), 7.74 (d, J = 1.3 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.42-7.34 (m, 1H), 7.32 (t, J = 1.8 Hz, 1H), 7.21 (t, J = 2.1 Hz, 1H), 6.71-6.62 (m, 1H), 3.97-3.82 (m, 4H), 3.29-3.13 (m, 4H) ppm. 169 426.51 0.64 H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.06 (s, 1H), 8.03-7.82 (m, 1H), 7.78-7.54 (m, 2H), 7.15 (s, 1H), 6.82 (s, 1H), 6.29 (s, 1H), 4.62 (dd, J = 7.9, 5.9 Hz, 2H), 4.38 (t, J = 6.1 Hz, 2H), 3.67 (d, J = 12.5 Hz, 2H), 2.85-2.56 (m, 3H), 2.21 (s, 3H), 1.88-1.53 (m, 3H), 1.14 (dt, J = 12.1, 8.7 Hz, 2H) ppm. 170 383.31 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.19 (s, 1H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 6.67 (d, J = 1.5 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H), 3.33 (dd, J = 11.6, 5.1 Hz, 4H), 1.91 (t, J = 6.6 Hz, 4H), 1.82 (ddd, J = 12.8, 8.2, 4.7 Hz, 1H), 0.92-0.83 (m, 2H), 0.77 (ddd, J = 9.5, 6.1, 3.3 Hz, 2H) ppm. 171 384.12 0.79 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.60 (dd, J = 8.7, 2.2 Hz, 2H), 7.24 (tt, J = 10.5, 8.2 Hz, 1H), 6.71 (d, J = 10.8 Hz, 2H), 5.81 (s, 1H), 4.72 (s, 4H), 3.94 (s, 4H), 2.19 (s, 3H) ppm. 172 419.4 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.05 (s, 1H), 7.93-7.73 (m, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 6.27 (s, 1H), 3.94 (d, J = 12.8 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.20 (t, J = 10.4 Hz, 2H), 3.15-2.94 (m, 4H), 2.69 (d, J = 23.0 Hz, 4H), 2.33 (ddd, J = 19.6, 12.8, 6.6 Hz, 1H), 2.22 (s, 3H), 1.97 (d, J = 11.1 Hz, 1H), 1.66 (d, J = 13.1 Hz, 1H), 1.58-1.26 (m, 2H) ppm. 173 441 0.68 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.35-7.14 (m, 3H), 6.77 (ddd, J = 8.7, 5.5, 2.3 Hz, 1H), 6.71-6.51 (m, 3H), 5.98 (s, 1H), 4.01 (t, J = 7.0 Hz, 2H), 3.75 (dd, J = 10.1, 5.2 Hz, 6H), 3.50-3.23 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.46 (s, 4H), 1.25 (t, J = 7.6 Hz, 4H—water peak) ppm. 174 393.48 0.59 1H NMR (300 MHz, DMSO-d6) δ 9.46 (d, J = 13.0 Hz, 1H), 9.29 (s, 1H), 9.11 (t, J = 10.6 Hz, 1H), 8.96 (d, J = 5.6 Hz, 1H), 7.72 (dd, J = 5.6, 1.2 Hz, 1H), 7.13 (s, 1H), 6.93 (s, 1H), 6.35 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.57-3.39 (m, 1H), 3.25-3.07 (m, 4H), 2.46-2.34 (m, 4H), 2.25 (s, 3H) ppm. 175 1H NMR (300 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.18 (s, 1H), 7.75-7.56 (m, 3H), 7.51 (s, 1H), 7.43 (s, 1H), 7.21 (t, J = 8.3 Hz, 1H), 6.74 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.52-3.41 (m, 1H), 3.29-3.20 (m, 4H), 2.47-2.38 (m, 4H) ppm. 176 377.5 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.29 (s, 1H), 9.08 (d, J = 0.9 Hz, 1H), 8.97 (d, J = 5.6 Hz, 1H), 7.71 (dd, J = 5.6, 1.1 Hz, 1H), 7.12 (s, 1H), 6.92 (s, 1H), 6.34 (s, 1H), 3.21-2.98 (m, 4H), 2.78-2.64 (m, 4H), 2.24 (s, 3H), 1.74-1.55 (m, 1H), 0.59-0.42 (m, 2H), 0.37 (dd, J = 7.9, 4.5 Hz, 2H) ppm. 177 361 0.64 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.42 (s, 1H), 9.24 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H), 7.92 (td, J = 8.9, 6.1 Hz, 1H), 7.78-7.54 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 6.76 (d, J = 11.8 Hz, 1H), 6.64 (s, 1H), 5.86 (d, J = 11.4 Hz, 1H), 4.29 (dd, J = 13.9, 6.7 Hz, 1H), 4.22 (s, 2H), 3.85 (d, J = 7.7 Hz, 2H) ppm. 178 428.44 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.16 (s, 1H), 7.75-7.53 (m, 2H), 7.25 (tt, J = 9.2, 2.2 Hz, 1H), 7.13 (s, 1H), 6.93 (s, 1H), 6.24 (s, 1H), 4.84 (t, J = 6.7 Hz, 1H), 4.56 (td, J = 6.5, 1.8 Hz, 2H), 4.46 (q, J = 6.0 Hz, 2H), 3.71-3.52 (m, 1H), 2.87 (dd, J = 10.3, 6.1 Hz, 1H), 2.76-2.57 (m, 2H), 2.48-2.39 (m, 1H), 2.36-2.14 (m, 4H), 1.94-1.70 (m, 1H) ppm. 179 363 0.6 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.25 (s, 1H), 9.09 (s, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.14 (s, 1H), 6.77 (s, 1H), 6.18 (s, 1H), 3.76 (d, J = 10.6 Hz, 2H), 3.46 (dd, J = 27.4, 6.9 Hz, 4H), 3.17 (dd, J = 29.4, 20.5 Hz, 2H), 2.80 (d, J = 4.7 Hz, 3H), 2.44-2.28 (m, 1H), 2.23 (s, 4H) ppm. 180 392 0.59 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 2H), 8.87 (d, J = 5.5 Hz, 1H), 7.77 (dd, J = 5.5, 1.1 Hz, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 6.79 (s, 1H), 6.70 (s, 1H), 4.79-4.53 (m, 4H), 3.60-3.42 (m, 1H), 2.88 (d, J = 9.2 Hz, 3H), 2.37 (s, 3H), 2.01 (d, J = 12.6 Hz, 1H), 1.96-1.38 (m, 6H) ppm. 181 408.15 3.2 1H NMR (400 MHz, DMSO-d6) δ 9.65 (d, J = 19.1 Hz, 1H), 9.27 (s, 1H), 8.17 (d, J = 7.8 Hz, 2H), 7.79 (dd, J = 22.6, 14.9 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.16 (s, 1H), 6.87 (t, J = 24.8 Hz, 1H), 6.27 (t, J = 41.6 Hz, 1H), 3.79-3.73 (m, 4H), 3.17-3.10 (m, 4H) ppm. 182 421 0.61 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.68 (dd, J = 8.6, 1.1 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 6.98 (s, 1H), 6.56 (s, 1H), 6.46 (s, 1H), 6.06 (s, 1H), 3.56 (s, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.34 (s, 3H), 2.91 (d, J = 11.5 Hz, 2H), 2.49-2.39 (m, 2H), 2.26 (s, 3H), 2.12 (d, J = 10.4 Hz, 3H), 1.85-1.73 (m, 2H), 1.57-1.44 (m, 2H) ppm. 183 443.22 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.07 (s, 1H), 8.02-7.81 (m, 1H), 7.80-7.50 (m, 2H), 6.82 (s, 2H), 6.05 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.72 (s, 3H), 3.56-3.38 (m, 1H), 3.23-3.00 (m, 4H), 2.41 (d, J = 4.3 Hz, 4H) ppm. 184 436.27 0.58 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 5.6 Hz, 1H), 7.26 (s, 1H), 7.03 (t, J = 2.1 Hz, 1H), 6.75 (s, 1H), 6.67 (s, 1H), 6.39 (s, 1H), 4.72 (dq, J = 12.6, 6.4 Hz, 4H), 3.66-3.51 (m, 1H), 3.36-3.25 (m, 4H), 2.60-2.48 (m, 4H), 1.96-1.83 (m, 1H), 1.05-0.90 (m, 2H), 0.79-0.67 (m, 2H) ppm. 185 439 0.68 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.23 (dd, J = 7.9, 2.2 Hz, 2H), 6.80 (s, 1H), 6.76 (dt, J = 8.7, 2.3 Hz, 1H), 6.71 (s, 1H), 6.54 (s, 1H), 6.02 (s, 1H), 4.69 (t, J = 6.7 Hz, 1H), 4.63 (t, J = 6.4 Hz, 1H), 4.56 (t, J = 6.2 Hz, 1H), 4.48 (t, J = 6.0 Hz, 1H), 4.31 (s, 1H), 4.05-3.92 (m, 1H), 3.58 (s, 1H), 3.45 (dd, J = 9.2, 2.0 Hz, 1H), 3.08 (dd, J = 19.0, 8.6 Hz, 2H), 2.93 (d, J = 9.3 Hz, 1H), 2.31 (s, 3H), 1.99 (dd, J = 18.2, 9.5 Hz, 2H) ppm. 186 345.41 0.67 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 8.2 Hz, 1H), 7.95-7.70 (m, 4H), 6.82-6.52 (m, 3H), 6.10 (s, 1H), 3.35 (t, J = 5.6 Hz, 4H), 2.35 (s, 3H), 2.16-1.86 (m, 4H) ppm. 187 480.33 0.51 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.45 (s, 1H), 7.34 (d, J = 9.5 Hz, 1H), 7.17 (s, 1H), 7.04 (t, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.60 (s, 1H), 6.41 (s, 1H), 4.71 (p, J = 6.2 Hz, 4H), 3.59 (dt, J = 12.0, 6.0 Hz, 2H), 3.55 (s, 2H), 3.37-3.27 (m, 4H), 2.51 (dt, J = 14.4, 6.1 Hz, 5H), 2.35 (s, 3H), 2.2 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H) ppm. 188 409.5 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 9.10 (s, 1H), 7.84-7.64 (m, 2H), 7.58 (td, J = 8.4, 6.5 Hz, 1H), 7.18 (td, J = 8.3, 1.6 Hz, 1H), 6.91 (s, 1H), 6.52 (s, 1H), 5.93 (s, 1H), 5.62 (d, J = 6.4 Hz, 1H), 4.56 (td, J = 6.4, 3.9 Hz, 2H), 4.45 (dd, J = 13.4, 6.0 Hz, 2H), 3.86 (s, 1H), 3.66-3.48 (m, 1H), 2.78 (dd, J = 17.4, 10.5 Hz, 1H), 2.61 (dd, J = 13.8, 8.2 Hz, 1H), 2.48-2.32 (m, 2H), 2.33-2.19 (m, 1H), 2.14 (s, 3H), 1.77-1.55 (m, 1H) ppm. 189 446.4 0.62 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.95 (s, 1H), 8.30 (d, J = 5.7 Hz, 1H), 7.73-7.67 (m, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 6.62 (t, J = 39.5 Hz, 2H), 4.77 (dt, J = 12.5, 6.5 Hz, 4H), 3.65 (dd, J = 14.1, 7.0 Hz, 1H), 3.39 (d, J = 4.0 Hz, 4H), 2.66 (s, 4H) ppm. 190 388.14 2.66 191 459.13 0.62 1H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 7.88-7.68 (m, 4H), 7.11 (s, 1H), 6.82 (s, 1H), 6.72 (s, 1H), 6.43 (s, 1H), 4.79-4.63 (m, 4H), 3.67-3.51 (m, 1H), 3.36-3.23 (m, 4H), 2.60-2.47 (m, 4H), 2.35 (s, 3H) ppm. 192 423.49 0.59 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.62-7.38 (m, 3H), 7.14-6.97 (m, 2H), 6.64 (s, 1H), 6.44 (s, 1H), 6.09 (s, 1H), 4.82-4.50 (m, 4H), 3.57 (s, 1H), 3.40 (s, 1H), 2.77 (d, J = 11.5 Hz, 2H), 2.37-2.22 (m, 3H), 2.19 (d, J = 11.4 Hz, 2H), 2.04 (dd, J = 13.4, 7.9 Hz, 2H), 1.61-1.49 (m, 2H) ppm. 193 430.31 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.19 (s, 1H), 7.71-7.57 (m, 3H), 7.26 (ddd, J = 9.4, 8.7, 4.0 Hz, 2H), 6.78 (s, 1H), 4.60 (t, J = 6.4 Hz, 2H), 4.52 (q, J = 5.9 Hz, 2H), 3.83-3.72 (m, 1H), 3.12 (dd, J = 24.3, 11.3 Hz, 1H), 3.00-2.82 (m, 2H), 2.74 (dd, J = 13.5, 8.8 Hz, 1H), 2.42-2.23 (m, 5H) ppm. 194 376 0.79 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.68 (dd, J = 8.5, 0.9 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.25 (s, 1H), 7.21 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 4.79 (d, J = 13.4 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.18 (td, J = 13.1, 2.4 Hz, 1H), 2.79-2.56 (m, 2H), 2.35 (s, 3H), 2.14 (s, 3H), 1.93 (t, J = 12.8 Hz, 2H), 1.76-1.57 (m, 3H) ppm. 195 393.48 0.59 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.20 (s, 1H), 9.05 (d, J = 1.4 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 2.6, 1.4 Hz, 1H), 7.16 (s, 1H), 6.93 (s, 1H), 6.34 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.52-4.41 (m, 2H), 3.46 (dt, J = 11.1, 5.6 Hz, 1H), 3.16 (dd, J = 5.1, 3.7 Hz, 4H), 2.47-2.38 (m, 4H), 2.26 (d, J = 8.1 Hz, 3H) ppm. 196 443.27 0.34 197 372.18 0.75 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.16 (s, 1H), 7.61 (dd, J = 8.6, 2.2 Hz, 2H), 7.32-7.20 (m, 1H), 6.86-6.75 (m, 2H), 6.08 (s, 1H), 4.78 (m, 2H), 4.61-4.49 (m, 3H), 2.80 (s, 3H), 2.22 (s, 3H) ppm. 198 441 0.69 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.57 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.37 (ddd, J = 6.3, 4.6, 3.2 Hz, 1H), 7.33-7.18 (m, 3H), 6.74-6.51 (m, 3H), 5.97 (s, 1H), 4.00 (t, J = 7.0 Hz, 2H), 3.87-3.65 (m, 5H), 3.35 (dd, J = 12.2, 5.5 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 2.46 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H) ppm. 199 455.35 0.66 1H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.43 (s, 1H), 9.17 (s, 1H), 7.74-7.48 (m, 2H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.04 (d, J = 33.2 Hz, 1H), 6.39 (s, 1H), 4.15 (d, J = 10.8 Hz, 1H), 3.91-3.48 (m, 6H), 3.45-3.07 (m, 6H), 2.22 (d, J = 20.2 Hz, 4H), 1.83 (dd, J = 18.9, 10.7 Hz, 2H), 1.70-1.45 (m, 1H) ppm. 200 427 0.77 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.16 (s, 1H), 7.61 (dd, J = 8.5, 2.1 Hz, 2H), 7.23 (dt, J = 9.3, 5.8 Hz, 2H), 6.88 (s, 1H), 6.37 (s, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.08-3.93 (m, 2H), 3.85-3.74 (m, 1H), 3.66 (dt, J = 15.8, 7.9 Hz, 2H), 3.45 (dd, J = 7.0, 5.1 Hz, 1H), 3.17 (dd, J = 13.1, 8.3 Hz, 1H), 2.78-2.55 (m, 2H), 2.78-2.55 (m, 2H), 2.24 (s, 3H) ppm. 201 424.44 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.04 (d, J = 13.4 Hz, 1H), 7.96-7.76 (m, 2H), 7.53-7.36 (m, 2H), 7.22 (s, 1H), 6.90 (s, 1H), 6.27 (s, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4.39-4.25 (m, 1H), 3.51-3.37 (m, 1H), 2.56 (d, J = 5.8 Hz, 2H), 2.28-2.18 (m, 3H), 2.14-1.89 (m, 4H), 1.73-1.55 (m, 2H) ppm. 202 411.27 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.12 (s, 1H), 8.03-7.86 (m, 1H), 7.75-7.58 (m, 2H), 6.87 (s, 1H), 6.78 (s, 1H), 4.16 (d, J = 12.6 Hz, 2H), 2.71 (t, J = 11.7 Hz, 2H), 1.83 (d, J = 4.7 Hz, 1H), 1.64 (d, J = 12.7 Hz, 3H), 1.13 (dd, J = 21.0, 9.5 Hz, 2H), 0.91 (d, J = 6.2 Hz, 3H), 0.86-0.75 (m, 4H) ppm. 203 371 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.15 (s, 1H), 7.71 (t, J = 8.7 Hz, 2H), 7.66-7.52 (m, 1H), 7.21 (t, J = 8.7 Hz, 1H), 7.01 (s, 1H), 6.95 (d, J = 11.3 Hz, 1H), 6.29 (d, J = 12.5 Hz, 1H), 3.16 (d, J = 4.4 Hz, 4H), 2.46 (m, 4H) ppm 204 437.35 0.58 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.59 (d, J = 0.6 Hz, 1H), 7.13-6.99 (m, 2H), 6.86 (d, J = 7.8 Hz, 2H), 6.44 (s, 1H), 4.82-4.61 (m, 4H), 4.51 (q, J = 7.1 Hz, 2H), 3.59 (p, J = 6.4 Hz, 1H), 3.38-3.26 (m, 4H), 2.62-2.47 (m, 4H), 2.36 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H) ppm. 205 425.36 0.91 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 6.98 (dt, J = 9.3, 2.1 Hz, 1H), 6.76 (s, 1H), 6.62-6.50 (m, 2H), 6.42 (s, 1H), 4.60 (dt, J = 12.1, 6.0 Hz, 1H), 3.34-3.23 (m, 4H), 2.69-2.57 (m, 4H), 2.39 (s, 3H), 2.34 (s, 3H), 1.40 (d, J = 6.1 Hz, 6H) ppm. 206 437.3 0.64 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.31 (s, 1H), 7.25 (dt, J = 9.4, 2.1 Hz, 1H), 7.19 (s, 1H), 6.90 (d, J = 9.3 Hz, 1H), 6.76 (s, 1H), 6.62 (s, 1H), 6.41 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.27 (m, 4H), 2.74 (q, J = 7.6 Hz, 2H), 2.57-2.48 (m, 4H), 2.34 (s, 3H), 1.35-1.25 (m, 3H) ppm. 207 391 0.62 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.14 (s, 1H), 8.59-8.38 (m, 1H), 8.08 (td, J = 8.0, 1.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 7.2, 5.4 Hz, 2H), 7.31 (s, 1H), 6.59 (s, 1H), 4.63-4.33 (m, 4H), 3.52-3.35 (m, 1H), 2.85-2.57 (m, 3H), 2.27 (s, 3H), 1.97-1.69 (m, 4H), 1.61 (dd, J = 25.1, 12.6 Hz, 1H), 1.42 (tt, J = 12.3, 6.2 Hz, 1H) ppm. 208 444.17 0.81 1H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.16 (s, 1H), 7.59-7.46 (m, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 6.95 (tt, J = 9.0, 2.2 Hz, 1H), 6.69 (s, 1H), 4.76 (dtd, J = 48.0, 10.0, 4.9 Hz, 1H), 4.19 (dt, J = 15.0, 7.3 Hz, 1H), 3.48 (dddd, J = 30.0, 24.1, 15.3, 6.7 Hz, 1H), 3.26-2.99 (m, 3H), 2.89-2.36 (m, 5H), 2.34 (s, 3H), 2.06-1.79 (m, 2H) ppm. 209 428.44 0.54 1H NMR (300 MHz, CDCl3) δ 9.03 (d, J = 2.2 Hz, 1H), 8.64 (dd, J = 4.8, 1.4 Hz, 1H), 8.40 (s, 1H), 8.01 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.49 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 7.34 (s, 1H), 7.15 (s, 1H), 6.91 (s, 1H), 6.64 (dd, J = 69.9, 43.5 Hz, 2H), 4.81-4.65 (m, 4H), 3.68-3.51 (m, 1H), 3.46-3.26 (m, 4H), 2.55 (d, J = 4.3 Hz, 4H) ppm. 210 423.12 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.17 (s, 1H), 7.05 (d, J = 2.2 Hz, 2H), 7.01 (d, J = 1.3 Hz, 1H), 6.76 (d, J = 1.3 Hz, 1H), 6.49 (t, J = 2.2 Hz, 1H), 3.82 (s, 6H), 3.74-3.60 (m, 4H), 3.38-3.34 (m, 4H), 1.89-1.76 (m, 1H), 0.94-0.71 (m, 4H) ppm. 211 379 0.58 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 8.41 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.94-7.83 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.23 (ddd, J = 7.1, 4.9, 1.3 Hz, 1H), 7.14 (s, 1H), 6.79 (d, J = 7.1 Hz, 2H), 6.43 (s, 1H), 3.76 (d, J = 12.3 Hz, 2H), 3.37 (s, 3H), 3.28 (d, J = 6.4 Hz, 2H), 2.77 (td, J = 12.2, 2.2 Hz, 2H), 2.33 (s, 3H), 1.85 (d, J = 12.7 Hz, 2H), 1.42 (dd, J = 11.7, 3.2 Hz, 2H) ppm. 212 345.16 0.66 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.05-7.73 (m, 3H), 7.71-7.39 (m, 3H), 7.11-6.97 (m, 1H), 6.63 (s, 1H), 3.63 (t, J = 6.4 Hz, 4H), 2.48-2.32 (s, 3H), 2.29-2.14 (m, 4H) ppm. 213 353 0.62 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.83-7.61 (m, 2H), 7.50 (dd, J = 10.7, 5.3 Hz, 2H), 7.45-7.30 (m, 1H), 7.06-6.86 (m, 1H), 6.81 (s, 1H), 6.73 (s, 1H), 6.25 (dd, J = 12.0, 2.1 Hz, 1H), 3.29 (s, 4H), 2.63 (s, 4H), 2.40 (s, 3H) ppm. 214 389.38 0.79 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.07 (s, 1H), 7.84 (dd, J = 8.6, 1.1 Hz, 2H), 7.65-7.49 (m, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.15 (s, 1H), 6.89 (s, 1H), 6.29 (s, 1H), 3.73 (s, 2H), 3.51-3.30 (m, 4H), 2.89-2.70 (m, 1H), 2.34-2.17 (m, 3H), 0.82-0.61 (m, 4H) ppm. 215 441.49 0.68 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.63 (s, 1H), 7.46-7.31 (m, 2H), 7.18 (d, J = 12.5 Hz, 1H), 6.95-6.74 (m, 2H), 6.43 (s, 1H), 4.68 (t, J = 8.0 Hz, 2H), 4.33 (d, J = 5.9 Hz, 2H), 4.01 (d, J = 47.0 Hz, 1H), 3.34-3.22 (m, 4H), 2.70-2.51 (m, 4H), 2.34 (s, 3H), 1.46 (s, 3H) ppm. 216 426.51 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.28 (d, J = 18.8 Hz, 1H), 9.15 (s, 1H), 7.72-7.53 (m, 2H), 7.34-7.15 (m, 2H), 6.79 (s, 1H), 6.31 (s, 1H), 4.62 (dd, J = 7.8, 5.9 Hz, 2H), 4.37 (t, J = 6.2 Hz, 2H), 3.69 (d, J = 12.5 Hz, 2H), 2.83-2.61 (m, 3H), 2.24 (d, J = 17.0 Hz, 3H), 1.86-1.70 (m, 1H), 1.65 (d, J = 12.7 Hz, 2H), 1.15 (dt, J = 11.9, 8.7 Hz, 2H) ppm. 217 426.23 0.57 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.05 (t, J = 2.2 Hz, 1H), 7.13 (d, J = 1.9 Hz, 1H), 6.78 (s, 1H), 6.70 (s, 1H), 6.43 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.40-3.24 (m, 4H), 2.59-2.46 (m, 4H), 2.35 (s, 3H) ppm. 218 473.13 0.64 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.68-7.57 (m, 2H), 7.31 (dd, J = 6.9, 4.8 Hz, 1H), 6.76 (s, 1H), 6.68 (s, 1H), 6.46 (s, 1H), 4.72 (dq, J = 12.5, 6.4 Hz, 4H), 3.66-3.52 (m, 1H), 3.38-3.29 (m, 3H), 2.64 (q, J = 7.6 Hz, 2H), 2.57-2.49 (m, 3H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 219 403 0.6 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.0 Hz, 1H), 6.90 (s, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 5.99 (s, 1H), 4.74 (d, J = 6.9 Hz, 2H), 4.66 (s, 2H), 4.41 (s, 1H), 4.12 (dd, J = 14.3, 7.1 Hz, 2H), 3.91 (s, 1H), 3.78-3.66 (m, 1H), 3.57-3.45 (m, 1H), 3.15 (d, J = 30.9 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 1H) ppm. 220 401.25 0.64 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.57-7.48 (m, 1H), 7.36 (dt, J = 9.3, 2.1 Hz, 1H), 7.17 (s, 1H), 7.14-7.02 (m, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 6.44 (s, 1H), 3.40-3.24 (m, 4H), 2.66 (s, 4H), 2.42 (s, 3H), 2.35 (s, 3H) ppm. 221 426.46 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 2H), 7.35 (s, 1H), 7.30-7.18 (m, 2H), 6.59 (s, 1H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 3.48-3.35 (m, 1H), 2.79 (d, J = 11.1 Hz, 2H), 2.47-2.34 (m, 1H), 2.27 (s, 3H), 1.93-1.55 (m, 6H) ppm. 222 363.19 0.64 1H NMR (300 MHz, CD3OD) δ 8.93 (s, 1H), 7.88-7.75 (m, 2H), 7.63-7.50 (m, 2H), 7.51-7.29 (m, 2H), 6.65 (s, 1H), 3.88 (dd, J = 6.0, 3.7 Hz, 4H), 3.57 (dd, J = 5.9, 3.8 Hz, 4H), 2.16 (tt, J = 8.3, 4.9 Hz, 1H), 1.33-1.20 (m, 2H), 0.98 (dt, J = 7.2, 4.8 Hz, 2H) ppm. 223 409.27 0.58 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.5 Hz, 1H), 8.01-7.87 (m, 1H), 7.35-7.28 (m, 3H), 7.12 (d, J = 1.9 Hz, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.42 (s, 1H), 4.72 (p, J = 6.4 Hz, 4H), 3.58 (p, J = 6.4 Hz, 1H), 3.33-3.24 (m, 4H), 2.58-2.48 (m, 4H), 2.35 (s, 3H) ppm. 224 392.44 0.53 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.29 (s, 1H), 8.69 (dd, J = 4.7, 1.5 Hz, 2H), 7.81 (dd, J = 4.7, 1.6 Hz, 2H), 7.14 (s, 1H), 6.91 (s, 1H), 6.33 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.45 (p, J = 6.3 Hz, 1H), 3.20-3.01 (m, 4H), 2.47-2.35 (m, 4H), 2.24 (s, 3H) ppm. 225 435.28 0.6 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.5 Hz, 1H), 7.97 (ddd, J = 7.3, 4.0, 1.4 Hz, 1H), 7.35-7.28 (m, 3H), 7.08 (t, J = 2.0 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.76 (s, 1H), 6.35 (s, 1H), 4.78-4.63 (m, 4H), 3.58 (p, J = 6.4 Hz, 1H), 3.33-3.22 (m, 4H), 2.54 (dd, J = 14.0, 9.0 Hz, 4H), 1.96-1.82 (m, 1H), 1.00-0.91 (m, 2H), 0.79-0.70 (m, 2H) ppm. 226 1H NMR (300 MHz, Acetone-d6) δ 9.16 (s, 1H), 8.91 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.91-7.75 (m, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 1.4 Hz, 2H), 6.83 (s, 1H), 3.41-3.23 (m, 4H), 2.87 (s, 2H), 2.60-2.45 (m, 4H), 2.29 (s, 3H) ppm. 227 391 0.71 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.05 (s, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.22 (s, 1H), 6.91 (s, 1H), 6.34 (s, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.11-3.91 (m, 2H), 3.84-3.71 (m, 1H), 3.71-3.50 (m, 2H), 3.16 (td, J = 12.7, 3.6 Hz, 1H), 2.65 (ddd, J = 28.7, 17.4, 7.7 Hz, 2H), 2.23 (s, 3H) ppm. 228 475.02 0.73 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.26 (dd, J = 7.6, 1.8 Hz, 2H), 7.15 (s, 1H), 6.87 (s, 1H), 6.81 (tt, J = 8.7, 2.2 Hz, 1H), 6.40 (s, 1H), 5.33 (dd, J = 4.8, 2.8 Hz, 2H), 4.48-4.40 (m, 2H), 3.42-3.22 (m, 8H), 2.06 (d, J = 3.8 Hz, 3H) ppm. 229 398.26 0.26 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.17 (s, 1H), 7.69-7.58 (m, 3H), 7.29-7.19 (m, 2H), 6.65 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.45-4.38 (m, 2H), 3.81-3.73 (m, 1H), 3.67 (t, J = 7.1 Hz, 2H), 3.64-3.56 (m, 1H), 3.19 (t, J = 6.6 Hz, 2H), 2.27 (s, 3H) ppm. 230 398.26 0.6 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.15 (s, 1H), 7.77-7.68 (m, 2H), 7.60 (td, J = 8.4, 6.4 Hz, 1H), 7.41-7.31 (m, 2H), 7.21 (td, J = 8.2, 1.6 Hz, 1H), 6.62 (d, J = 9.6 Hz, 1H), 4.59 (td, J = 6.5, 2.0 Hz, 2H), 4.51 (td, J = 6.0, 1.6 Hz, 2H), 3.69-3.60 (m, 1H), 2.95-2.87 (m, 1H), 2.69-2.61 (m, 2H), 2.49-2.43 (m, 2H), 2.34-2.21 (m, 1H), 1.78 (td, J = 14.9, 7.4 Hz, 1H) ppm. 231 453.42 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.05 (s, 1H), 8.02-7.84 (m, 1H), 7.76-7.51 (m, 2H), 7.12 (s, 1H), 6.88 (s, 1H), 6.30 (s, 1H), 3.30-3.16 (m, 2H), 3.17-2.98 (m, 4H), 2.85-2.68 (m, 4H), 2.22 (s, 3H) ppm. 232 428.3 0.59 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.13 (s, 2H), 7.04 (d, J = 15.7 Hz, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 6.47 (s, 1H), 4.81-4.64 (m, 4H), 3.66-3.50 (m, 1H), 3.38-3.26 (m, 4H), 2.53 (dd, J = 13.3, 8.4 Hz, 4H), 2.35 (d, J = 10.7 Hz, 3H) ppm. 233 435.51 0.63 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.61 (dt, J = 7.1, 3.2 Hz, 1H), 7.54 (dt, J = 5.7, 3.2 Hz, 1H), 7.50-7.42 (m, 2H), 7.07 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 6.39 (s, 1H), 4.80-4.61 (m, 4H), 4.49 (s, 2H), 3.57 (p, J = 6.4 Hz, 1H), 3.43 (s, 3H), 3.33-3.21 (m, 4H), 2.59-2.44 (m, 4H), 2.33 (s, 3H) ppm. 234 373.36 0.84 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.75-7.66 (m, 2H), 7.53 (ddd, J = 6.8, 4.9, 2.4 Hz, 3H), 7.46-7.35 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.08-6.02 (m, 1H), 6.00-5.94 (m, 1H), 4.96-4.80 (m, 8H) ppm. 235 462.13 0.86 1H NMR (400 MHz, CD3OD) δ 8.88 (s, 1H), 7.70-7.42 (m, 3H), 7.34 (s, 1H), 6.95 (tt, J = 9.0, 2.3 Hz, 1H), 6.73 (s, 1H), 4.68 (ddt, J = 19.4, 12.5, 4.8 Hz, 3H), 4.16-3.66 (m, 3H), 3.19-2.86 (m, 3H), 2.46-2.10 (m, 5H), 1.24-1.14 (m, 2H) ppm. 236 421.51 0.58 1H NMR (300 MHz, CDCl3) δ 11.33 (d, J = 12.2 Hz, 1H), 9.26 (d, J = 1.6 Hz, 1H), 8.13 (dd, J = 4.7, 1.7 Hz, 1H), 8.02 (d, J = 12.0 Hz, 1H), 7.88 (d, J = 4.7 Hz, 1H), 6.60 (dd, J = 8.6, 1.9 Hz, 3H), 4.83-4.62 (m, 4H), 3.68-3.50 (m, 1H), 3.38-3.20 (m, 4H), 2.67-2.45 (m, 6H), 1.68 (dq, J = 14.7, 7.4 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H) ppm. 237 405.33 0.62 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.77-7.65 (m, 2H), 7.53 (dd, J = 10.7, 5.1 Hz, 2H), 7.42-7.29 (m, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.62 (s, 1H), 4.74 (t, J = 6.4 Hz, 4H), 3.63 (p, J = 6.5 Hz, 1H), 3.03 (t, J = 4.7 Hz, 4H), 2.56 (s, 4H), 2.30 (s, 3H), 2.21 (d, J = 16.5 Hz, 3H) ppm. 238 386.19 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.16 (s, 1H), 7.60 (dd, J = 8.6, 2.1 Hz, 2H), 7.31-7.17 (m, 2H), 6.77 (s, 1H), 6.31 (s, 1H), 4.68 (d, J = 4.3 Hz, 1H), 3.63 (m, 1H), 3.53 (d, J = 12.9 Hz, 2H), 2.85 (t, J = 10.1 Hz, 2H), 2.21 (s, 3H), 1.81 (d, J = 11.1 Hz, 2H), 1.47 (m, 2H) ppm. 239 392.44 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.06 (s, 1H), 7.95-7.82 (m, 1H), 7.55 (t, J = 8.0 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 6.21 (s, 1H), 4.83 (s, 1H), 4.57 (td, J = 6.5, 1.8 Hz, 2H), 4.47 (dd, J = 10.4, 5.9 Hz, 2H), 3.64 (s, 1H), 2.99-2.83 (m, 1H), 2.63 (d, J = 9.9 Hz, 2H), 2.48-2.41 (m, 1H), 2.40-2.16 (m, 4H), 1.86 (d, J = 5.1 Hz, 1H) ppm. 240 358.13 0.81 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.15 (s, 1H), 7.66 (dd, J = 8.7, 2.2 Hz, 2H), 7.32-7.15 (m, 1H), 6.83 (s, 1H), 6.57 (s, 1H), 6.28 (d, J = 5.6 Hz, 1H), 5.82 (s, 1H), 4.84 (t, J = 5.9 Hz, 2H), 4.47 (m, 3H), 2.15 (s, 3H) ppm. 241 392.13 3.61 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.26 (s, 1H), 8.26-8.04 (m, 2H), 7.80 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 6.88 (s, 1H), 6.67 (d, J = 11.7 Hz, 1H), 5.86 (t, J = 16.9 Hz, 1H), 3.25 (s, 4H), 1.97 (t, J = 6.5 Hz, 4H) ppm. 242 386.24 0.7 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.16 (s, 1H), 7.84 (s, 1H), 7.65 (dd, J = 8.5, 2.1 Hz, 2H), 7.28-7.18 (m, 1H), 7.12 (s, 1H), 6.86 (s, 1H), 5.15 (s, 1H), 2.89 (d, J = 9.6 Hz, 1H), 2.83-2.65 (m, 3H), 2.34 (s, 3H), 2.28 (s, 3H), 2.20-2.10 (m, 1H), 2.07-1.99 (m, 1H) ppm. 243 455.4 0.64 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.43 (s, 1H), 9.18 (s, 1H), 7.72-7.55 (m, 2H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.40 (s, 1H), 4.00 (dd, J = 11.4, 3.8 Hz, 2H), 3.76 (d, J = 9.6 Hz, 2H), 3.61 (d, J = 8.0 Hz, 2H), 3.46 (s, 1H), 3.31 (t, J = 11.3 Hz, 2H), 3.24-3.08 (m, 4H), 2.28 (d, J = 12.6 Hz, 3H), 2.04 (t, J = 14.2 Hz, 2H), 1.92-1.62 (m, 2H) ppm. 244 411.27 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.21 (s, 1H), 7.70-7.55 (m, 2H), 7.28 (dd, J = 10.5, 8.3 Hz, 1H), 6.90 (s, 1H), 6.76 (s, 1H), 4.17 (d, J = 13.2 Hz, 2H), 2.73 (t, J = 11.4 Hz, 2H), 1.85 (d, J = 4.7 Hz, 1H), 1.64 (d, J = 12.1 Hz, 3H), 1.10 (d, J = 11.1 Hz, 2H), 0.91 (d, J = 6.2 Hz, 3H), 0.88-0.69 (m, 4H) ppm. 245 425.27 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.62 (d, J = 24.0 Hz, 1H), 9.16 (s, 1H), 7.06 (d, J = 2.2 Hz, 2H), 6.79 (s, 1H), 6.63 (s, 1H), 6.49 (t, J = 2.2 Hz, 1H), 5.40 (d, J = 53.9 Hz, 1H), 3.83 (s, 6H), 3.73-3.46 (m, 3H), 3.43-3.34 (m, 1H), 2.23 (s, 2H), 1.80 (s, 1H), 0.88 (d, J = 4.7 Hz, 2H), 0.79 (d, J = 7.7 Hz, 2H) ppm. 246 398.29 0.96 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.66-7.55 (m, 2H), 7.43 (ddd, J = 8.3, 5.4, 1.8 Hz, 2H), 7.28 (ddd, J = 7.4, 3.9, 1.2 Hz, 1H), 6.98 (dt, J = 14.2, 1.9 Hz, 2H), 6.78 (s, 1H), 6.45 (t, J = 1.9 Hz, 1H), 3.67 (d, J = 12.4 Hz, 2H), 3.29 (s, 3H), 3.20 (d, J = 6.3 Hz, 2H), 2.71 (td, J = 12.4, 2.4 Hz, 2H), 1.85-1.61 (m, 3H), 1.42-1.21 (m, 2H) ppm. 247 349 2.12 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.75-7.60 (m, 2H), 7.49 (dd, J = 10.7, 5.2 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.13 (s, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 6.39 (s, 1H), 3.36-3.15 (m, 4H), 2.68-2.50 (m, 4H), 2.37 (s, 3H), 2.32 (s, 3H) ppm. 248 390 0.61 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.15 (s, 1H), 6.76 (s, 1H), 6.65 (s, 1H), 4.75-4.55 (m, 4H), 3.50 (p, J = 6.4 Hz, 1H), 2.84 (dd, J = 18.4, 7.1 Hz, 3H), 2.35 (s, 3H), 2.00 (d, J = 12.5 Hz, 1H), 1.95-1.63 (m, 5H), 1.50 (dd, J = 22.9, 10.4 Hz, 1H) ppm. 249 410.49 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.32 (s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 5.8 Hz, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 6.53 (s, 1H), 5.95 (s, 1H), 5.68 (d, J = 6.5 Hz, 1H), 4.68-4.52 (m, 2H), 4.44 (dt, J = 19.2, 9.6 Hz, 2H), 3.87 (s, 1H), 3.72-3.50 (m, 1H), 2.78 (dd, J = 18.4, 10.3 Hz, 1H), 2.62 (d, J = 5.9 Hz, 1H), 2.41 (dd, J = 13.7, 8.3 Hz, 2H), 2.32-2.20 (m, 1H), 2.16 (s, 3H), 1.67 (dd, J = 12.0, 5.4 Hz, 1H) ppm. 250 406.39 0.66 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J = 2.2 Hz, 1H), 8.64 (dd, J = 4.8, 1.4 Hz, 1H), 8.40 (s, 1H), 8.03 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.50 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 7.30 (d, J = 1.4 Hz, 2H), 6.80 (s, 1H), 6.76 (s, 1H), 4.12 (dd, J = 10.3, 3.0 Hz, 4H), 3.57 (td, J = 11.3, 3.2 Hz, 4H), 2.79 (ddd, J = 15.6, 10.5, 5.0 Hz, 2H), 1.96-1.77 (m, 8H) ppm. 251 406.44 0.69 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.73-7.65 (m, 3H), 7.52 (ddd, J = 8.3, 5.3, 1.8 Hz, 3H), 7.42-7.33 (m, 1H), 7.19 (t, J = 2.1 Hz, 1H), 6.89 (t, J = 1.5 Hz, 1H), 6.74 (s, 1H), 6.46 (d, J = 1.6 Hz, 1H), 4.11 (dd, J = 10.3, 3.1 Hz, 2H), 3.92-3.88 (m, 4H), 3.55 (td, J = 11.4, 2.9 Hz, 3H), 3.26-3.22 (m, 4H), 2.81-2.68 (m, 1H), 1.91-1.80 (m, 4H) ppm. 252 475.11 0.63 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.67 (s, 1H), 7.56 (ddd, J = 23.0, 11.6, 5.0 Hz, 2H), 7.27 (s, 1H), 7.19 (dt, J = 21.6, 7.9 Hz, 1H), 6.73 (d, J = 10.2 Hz, 2H), 6.42 (s, 1H), 4.79-4.60 (m, 4H), 3.58 (p, J = 6.4 Hz, 1H), 3.38-3.21 (m, 4H), 2.61-2.44 (m, 4H), 2.34 (s, 3H) ppm. 253 393.39 0.64 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.67 (dt, J = 12.4, 6.4 Hz, 2H), 7.52 (dd, J = 10.6, 5.1 Hz, 2H), 7.45-7.33 (m, 1H), 7.13 (s, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 6.40 (s, 1H), 3.29 (s, 4H), 2.87 (s, 4H), 2.59-2.37 (m, 2H), 2.36 (d, J = 8.9 Hz, 3H), 1.24 (s, 5H) ppm. 254 423.31 0.59 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.62 (d, J = 0.6 Hz, 1H), 7.08 (dd, J = 3.5, 1.3 Hz, 2H), 6.92 (s, 1H), 6.84 (s, 1H), 6.44 (s, 1H), 4.72 (p, J = 6.4 Hz, 4H), 4.07 (s, 3H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.26 (m, 4H), 2.54 (dd, J = 11.2, 6.3 Hz, 4H), 2.36 (s, 3H) ppm. 255 395.26 0.64 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.23 (s, 1H), 7.15 (d, J = 9.4 Hz, 1H), 7.11 (s, 1H), 6.80 (d, J = 9.1 Hz, 1H), 6.62 (d, J = 21.7 Hz, 1H), 6.57 (s, 1H), 6.32 (s, 1H), 3.26-3.16 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 2.56-2.48 (m, 4H), 2.29 (s, 3H), 2.25 (s, 3H), 1.28-1.17 (m, 3H) ppm. 257 421.31 3.17 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.72 (m, 2H), 7.67-7.56 (m, 1H), 7.53 (d, J = 12.3 Hz, 2H), 7.24 (td, J = 11.8, 5.1 Hz, 1H), 6.86 (s, 1H), 3.88 (m, 2H), 3.55 (m, 2H), 3.28-3.12 (m, 4H), 2.86 (s, 3H) ppm. 258 425.22 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.35 (d, J = 7.3 Hz, 1H), 9.13 (s, 1H), 7.84-7.65 (m, 2H), 7.60 (td, J = 8.3, 6.4 Hz, 1H), 7.19 (td, J = 8.3, 1.4 Hz, 1H), 6.84 (d, J = 2.0 Hz, 2H), 6.05 (d, J = 1.9 Hz, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.72 (s, 3H), 3.55-3.40 (m, 1H), 3.24-2.97 (m, 4H), 2.37 (dd, J = 24.8, 20.2 Hz, 4H) ppm. 259 349 0.59 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.19 (s, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 6.40 (s, 1H), 3.60 (t, J = 9.6 Hz, 2H), 3.22-2.93 (m, 3H), 2.75 (td, J = 11.5, 3.5 Hz, 1H), 2.54-2.36 (m, 1H), 2.33 (s, 3H), 1.57 (s, 1H), 1.15 (d, J = 6.3 Hz, 3H) ppm. 260 376.29 0.6 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.06 (s, 1H), 7.85 (dd, J = 8.6, 1.0 Hz, 2H), 7.58-7.52 (m, 2H), 7.50 (s, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.21 (s, 1H), 6.60 (s, 1H), 4.59 (t, J = 6.5 Hz, 2H), 4.51 (td, J = 6.0, 2.0 Hz, 2H), 3.65 (dt, J = 12.4, 6.2 Hz, 1H), 3.29-3.20 (m, 1H), 2.95 (t, J = 8.4 Hz, 1H), 2.70 (dd, J = 14.8, 8.0 Hz, 1H), 2.61 (td, J = 8.6, 5.4 Hz, 1H), 2.47-2.41 (m, 1H), 2.30-2.21 (m, 4H), 1.79 (dt, J = 14.4, 8.1 Hz, 1H) ppm. 261 410 0.67 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.30-7.22 (m, 3H), 7.21 (s, 1H), 7.16 (s, 1H), 6.78 (tt, J = 8.7, 2.3 Hz, 1H), 6.71 (s, 1H), 6.66 (s, 1H), 3.17 (d, J = 11.5 Hz, 2H), 2.50 (tt, J = 12.0, 4.1 Hz, 1H), 2.35 (s, 3H), 2.28 (dd, J = 11.7, 2.6 Hz, 2H), 1.83 (dd, J = 14.0, 7.0 Hz, 2H), 1.75 (dd, J = 12.5, 3.3 Hz, 1H), 1.69-1.57 (m, 1H), 0.47 (d, J = 6.5 Hz, 4H) ppm. 262 384.23 0.57 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.06 (t, J = 2.2 Hz, 1H), 7.13 (s, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 6.44 (s, 1H), 3.34-3.21 (m, 4H), 2.60 (dd, J = 18.9, 13.9 Hz, 4H), 2.38 (s, 3H), 2.35 (s, 3H) ppm. 263 386.15 0.52 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.12 (s, 1H), 8.07-7.90 (m, 1H), 7.78-7.58 (m, 2H), 6.93 (s, 1H), 6.72 (s, 1H), 3.51-3.36 (m, 4H), 2.39 (dd, J = 19.5, 14.6 Hz, 4H), 2.25 (s, 3H), 2.22 (s, 3H) ppm. 264 455.15 0.68 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.26 (dd, J = 8.0, 2.2 Hz, 2H), 7.13 (t, J = 2.0 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.78 (dt, J = 8.7, 2.3 Hz, 1H), 6.66 (s, 1H), 6.47 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.38-3.18 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 2.61-2.48 (m, 4H), 1.44 (s, 3H), 1.28 (t, J = 7.6 Hz, 4H) ppm. 265 373.14 0.62 1H NMR (300 MHz, CD3OD) δ 8.95 (s, 1H), 7.86 (ddd, J = 11.3, 6.9, 2.6 Hz, 1H), 7.68 (ddt, J = 8.3, 4.2, 2.2 Hz, 1H), 7.61-7.34 (m, 2H), 6.90 (s, 1H), 3.87 (dd, J = 6.0, 3.8 Hz, 4H), 3.66 (s, 1H), 3.57 (dd, J = 6.1, 3.7 Hz, 4H), 2.51 (s, 3H) ppm. 266 412 0.84 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.17 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.46 (s, 1H), 7.33 (d, J = 15.0 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1H), 6.63 (d, J = 21.7 Hz, 1H), 4.47 (t, J = 10.7 Hz, 1H), 3.85 (t, J = 11.0 Hz, 1H), 3.05 (dd, J = 23.7, 10.5 Hz, 1H), 2.70-2.59 (m, 1H), 2.28 (s, 3H), 2.03 (s, 3H), 1.95 (d, J = 11.3 Hz, 1H), 1.82-1.61 (m, 3H), 1.61-1.35 (m, 2H) ppm. 267 385.29 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 9.15 (s, 1H), 7.60 (dd, J = 8.7, 2.2 Hz, 2H), 7.24 (tt, J = 10.4, 8.1 Hz, 1H), 6.90 (m, 1H), 6.60 (m, 1H), 5.90 (m, 1H), 3.43 (dd, J = 9.0, 6.1 Hz, 1H), 3.32-3.16 (m, 3H), 3.01 (dd, J = 9.1, 4.7 Hz, 1H), 2.33 (s, 3H), 2.20 (s, 3H), 2.14-2.01 (m, 1H), 1.79 (m, 1H) ppm. 268 416.26 0.6 1H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.20 (s, 1H), 7.70-7.58 (m, 2H), 7.40 (s, 1H), 7.29 (ddt, J = 18.7, 9.3, 2.2 Hz, 2H), 6.64 (d, J = 9.9 Hz, 1H), 4.58 (td, J = 6.5, 1.9 Hz, 2H), 4.50 (t, J = 5.7 Hz, 2H), 3.69-3.58 (m, 1H), 2.97-2.88 (m, 1H), 2.69-2.61 (m, 2H), 2.44 (dd, J = 8.9, 7.3 Hz, 2H), 2.35-2.19 (m, 1H), 1.78 (dt, J = 15.1, 7.2 Hz, 1H) ppm. 269 338.1 2.33 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 9.00 (s, 1H), 7.94-7.76 (m, 2H), 7.47-7.33 (m, 2H), 6.84 (s, 1H), 6.66 (s, 1H), 5.91 (s, 1H), 3.41-3.27 (m, 4H), 2.20 (s, 3H), 2.08-1.85 (m, 4H) ppm. 270 308 0.61 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J = 2.5 Hz, 1H), 8.62 (dd, J = 4.8, 1.3 Hz, 1H), 8.40 (s, 1H), 8.04 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.56-7.42 (m, 2H), 6.88 (d, J = 5.9 Hz, 2H), 5.09 (dd, J = 8.3, 6.0 Hz, 2H), 4.82 (t, J = 6.3 Hz, 2H), 4.30-4.12 (m, 1H), 2.40 (s, 3H) ppm. 271 407.25 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.15 (s, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 7.16 (s, 1H), 6.92 (s, 1H), 6.34 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.45 (dt, J = 12.7, 6.5 Hz, 1H), 3.25-3.03 (m, 4H), 2.56 (s, 3H), 2.40 (dd, J = 15.5, 10.8 Hz, 4H), 2.26 (d, J = 9.5 Hz, 3H) ppm. 272 338.13 2.38 1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 41.3 Hz, 1H), 9.14 (s, 1H), 7.73 (s, 2H), 7.59 (dt, J = 14.9, 7.4 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.85 (s, 1H), 5.98 (s, 1H), 3.36 (s, 3H), 2.24 (s, 3H), 1.95 (d, J = 51.8 Hz, 3H) ppm. 273 384 0.26 274 363.42 0.62 1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.33 (s, 1H), 9.09 (s, 1H), 7.98-7.75 (m, 2H), 7.65-7.45 (m, 2H), 7.46-7.33 (m, 1H), 7.21 (s, 1H), 6.99 (d, J = 15.5 Hz, 1H), 6.38 (s, 1H), 3.74 (d, J = 10.6 Hz, 2H), 3.57 (d, J = 8.9 Hz, 2H), 3.14 (dt, J = 19.6, 9.9 Hz, 6H), 2.26 (d, J = 7.7 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H) ppm. 275 392.44 0.54 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.19-9.05 (m, 2H), 8.55 (dd, J = 4.7, 1.4 Hz, 1H), 8.20 (ddd, J = 8.3, 2.6, 1.4 Hz, 1H), 7.60 (ddd, J = 8.4, 4.8, 0.6 Hz, 1H), 7.15 (s, 1H), 6.89 (s, 1H), 6.31 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.45 (p, J = 6.3 Hz, 1H), 3.16 (dd, J = 8.5, 5.1 Hz, 4H), 2.45-2.32 (m, 4H), 2.23 (s, 3H) ppm. 276 441.17 0.61 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.6 Hz, 1H), 7.25 (ddd, J = 8.3, 5.3, 2.6 Hz, 1H), 7.20-7.12 (m, 1H), 7.11 (t, J = 2.1 Hz, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 6.46 (s, 1H), 4.80-4.61 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.24 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.58-2.47 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 277 449.32 0.56 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 7.35 (d, J = 5.4 Hz, 1H), 7.01 (t, J = 2.0 Hz, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.39 (s, 1H), 4.72 (dt, J = 14.5, 6.4 Hz, 4H), 4.10 (d, J = 6.2 Hz, 3H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.23 (m, 4H), 2.62-2.48 (m, 4H), 1.97-1.81 (m, 1H), 1.03-0.92 (m, 2H), 0.81-0.66 (m, 2H) ppm. 278 441.45 0.6 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 18.3 Hz, 1H), 7.69-7.55 (m, 1H), 7.47-7.29 (m, 2H), 6.95 (d, J = 11.2 Hz, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 6.10 (s, 1H), 4.96 (s, 2H), 4.76 (t, J = 7.3 Hz, 2H), 3.96 (s, 2H), 3.68-3.45 (m, 2H), 3.24 (s, 2H), 2.57 (d, J = 40.5 Hz, 2H), 2.11 (dd, J = 36.1, 13.1 Hz, 2H) ppm. 279 412.33 0.64 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 13.2 Hz, 1H), 7.16 (s, 1H), 7.08 (s, 1H), 6.71 (dd, J = 10.6, 8.6 Hz, 3H), 6.35 (s, 1H), 4.42 (s, 5H), 3.12 (dd, J = 14.7, 9.2 Hz, 4H), 2.21 (d, J = 22.0 Hz, 3H), 2.07-1.87 (m, 5H) ppm. 280 391 66 281 344.8 0.69 1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 8.03 (dt, J = 2.2, 0.9 Hz, 1H), 7.93 (s, 1H), 7.72-7.56 (m, 2H), 6.77 (s, 1H), 6.62 (s, 2H), 6.10 (s, 1H), 3.37 (d, J = 6.1 Hz, 4H), 2.35 (s, 3H), 2.05 (t, J = 5.1 Hz, 4H) ppm. 282 442.15 0.73 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.17 (s, 1H), 7.77-7.53 (m, 2H), 7.34 (s, 1H), 7.30-7.19 (m, 2H), 6.59 (s, 1H), 4.55 (dd, J = 12.7, 6.3 Hz, 3H), 4.44 (td, J = 6.0, 2.3 Hz, 2H), 3.65 (d, J = 4.4 Hz, 1H), 3.64-3.23 (m, 6H), 2.86 (dd, J = 10.2, 3.5 Hz, 1H), 2.70 (d, J = 10.8 Hz, 1H), 2.27 (s, 3H), 2.21 (d, J = 4.5 Hz, 1H), 1.80 (dd, J = 11.2, 8.8 Hz, 1H), 1.73-1.49 (m, 3H) ppm. 283 361 68 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.75 (d, J = 2.2 Hz, 1H), 7.87 (td, J = 8.9, 6.0 Hz, 1H), 7.64 (ddd, J = 11.6, 9.0, 2.7 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 6.78 (d, J = 11.9 Hz, 1H), 6.49 (d, J = 7.2 Hz, 1H), 5.80-5.63 (m, 1H), 3.99 (dd, J = 14.9, 7.8 Hz, 2H), 3.83-3.69 (m, 1H), 3.35 (dd, J = 14.9, 7.8 Hz, 2H—partially obscured by MeOH) ppm. 284 441 0.68 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.33-7.16 (m, 5H), 6.93 (s, 1H), 6.81-6.69 (m, 1H), 6.60 (s, 1H), 6.47 (s, 1H), 6.03 (s, 1H), 3.78 (t, J = 4.7 Hz, 3H), 3.69-3.55 (m, 1H), 3.50 (t, J = 8.4 Hz, 1H), 3.37 (dt, J = 16.4, 8.1 Hz, 1H), 3.26 (t, J = 8.5 Hz, 1H), 3.04-2.87 (m, 1H), 2.58 (d, J = 20.4 Hz, 4H), 2.32 (s, 2H), 2.30-2.17 (m, 1H), 1.95 (dd, J = 19.9, 10.7 Hz, 1H). 285 493.38 0.94 H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 7.00-6.92 (m, 1H), 6.71 (s, 1H), 6.57 (d, J = 10.7 Hz, 2H), 6.36 (s, 1H), 4.79-4.67 (m, 4H), 4.68-4.53 (m, 1H), 3.68-3.50 (m, 1H), 3.41-3.23 (m, 4H), 2.61-2.44 (m, 4H), 1.97-1.82 (m, 1H), 1.40 (d, J = 6.0 Hz, 6H), 0.96 (dt, J = 6.2, 4.3 Hz, 2H), 0.84-0.67 (m, 2H) ppm. 286 463.32 0.6 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.59 (d, J = 0.8 Hz, 1H), 7.06 (t, J = 2.0 Hz, 1H), 7.03 (d, J = 0.8 Hz, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.37 (s, 1H), 4.72 (dq, J = 12.7, 6.4 Hz, 4H), 4.51 (q, J = 7.1 Hz, 2H), 3.66-3.48 (m, 1H), 3.36-3.25 (m, 4H), 2.61-2.46 (m, 4H), 1.98-1.84 (m, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.06-0.90 (m, 2H), 0.79-0.68 (m, 2H) ppm. 287 459.13 0.62 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.69-7.53 (m, 2H), 7.31 (s, 1H), 6.70 (s, 2H), 6.43 (s, 1H), 4.72 (dq, J = 12.5, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.37-3.25 (m, 4H), 2.60-2.47 (m, 4H), 2.35 (s, 3H) ppm. 288 435.42 0.68 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.21 (s, 1H), 9.01 (d, J = 1.2 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 2.5, 1.4 Hz, 1H), 7.29 (s, 1H), 7.12 (s, 1H), 6.53 (s, 1H), 4.58 (t, J = 6.4 Hz, 2H), 4.55-4.36 (m, 3H), 3.56-3.40 (m, 1H), 3.16 (d, J = 4.7 Hz, 4H), 2.42 (t, J = 9.0 Hz, 4H), 1.29 (s, 9H) ppm. 289 419.4 0.63 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.69 (dd, J = 8.5, 1.1 Hz, 2H), 7.52 (dd, J = 10.6, 5.1 Hz, 2H), 7.37 (dt, J = 9.1, 4.2 Hz, 1H), 7.13 (s, 1H), 6.82 (s, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 4.08 (dd, J = 11.0, 4.0 Hz, 2H), 3.43 (td, J = 11.8, 1.8 Hz, 2H), 3.34-3.19 (m, 4H), 2.81-2.69 (m, 4H), 2.59-2.42 (m, 1H), 1.85 (dd, J = 12.4, 1.8 Hz, 2H), 1.65 (qd, J = 12.4, 4.5 Hz, 3H) ppm. 290 389.38 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.04 (s, 1H), 7.82 (dd, J = 8.6, 1.1 Hz, 2H), 7.55 (dd, J = 10.7, 5.2 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.14 (s, 1H), 6.88 (s, 1H), 6.28 (s, 1H), 3.20-3.02 (m, 4H), 2.74 (p, J = 8.0 Hz, 1H), 2.48-2.32 (m, 4H), 2.24 (d, J = 15.9 Hz, 3H), 2.07-1.91 (m, 2H), 1.91-1.74 (m, 2H), 1.74-1.51 (m, 2H) ppm. 291 411.16 0.51 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 3.7 Hz, 1H), 7.40 (s, 1H), 6.77 (s, 1H), 6.66 (s, 1H), 6.43 (s, 1H), 4.80-4.66 (m, 3H), 3.60 (dd, J = 12.6, 6.1 Hz, 1H), 3.39-3.25 (m, 3H), 2.60-2.46 (m, 3H), 2.34 (s, 3H) ppm. 292 387 0.63 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.67 (d, J = 7.7 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 6.84 (s, 1H), 6.60 (s, 1H), 6.57 (s, 1H), 6.04 (s, 1H), 4.25 (s, 1H), 3.64 (s, 1H), 3.56-3.41 (m, 2H), 3.12 (d, J = 9.5 Hz, 1H), 2.90 (d, J = 9.6 Hz, 1H), 2.30 (s, 3H), 2.01-1.87 (m, 3H), 0.41 (dd, J = 13.4, 6.3 Hz, 4H) ppm. 293 400.24 0.64 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.18-7.15 (m, 1H), 7.10 (s, 1H), 6.70 (ddt, J = 8.6, 4.5, 2.2 Hz, 2H), 6.63 (s, 1H), 6.35 (s, 1H), 3.68 (dd, J = 11.8, 3.8 Hz, 1H), 3.41-3.35 (m, 4H), 2.84-2.68 (m, 2H), 2.25 (s, 3H), 2.05-1.96 (m, 1H), 1.81 (ddd, J = 17.2, 8.3, 4.3 Hz, 1H), 1.70-1.51 (m, 3H), 1.45-1.33 (m, 1H) ppm. 294 404.5 0.66 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.71 (dd, J = 8.6, 1.1 Hz, 2H), 7.57-7.48 (m, 2H), 7.38 (dt, J = 8.0, 3.7 Hz, 1H), 7.28-7.25 (m, 1H), 7.23 (s, 1H), 6.72 (s, 1H), 6.67 (s, 1H), 4.68 (s, 2H), 4.27 (d, J = 5.7 Hz, 2H), 2.71 (s, 2H), 2.51 (s, 1H), 2.27 (d, J = 63.5 Hz, 5H), 1.91 (s, 4H), 1.47 (s, 3H) ppm. 295 372.1 0.75 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.19 (s, 1H), 7.74-7.54 (m, 4H), 7.34 (s, 1H), 7.30-7.18 (m, 1H), 6.70 (s, 1H), 5.60-5.50 (m, 1H), 3.90 (t, J = 8.6 Hz, 1H), 3.28 (m, 1H), 2.31 (s, 3H) ppm. 296 365.17 0.62 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.50 (t, J = 7.9 Hz, 2H), 7.35 (dd, J = 18.9, 11.5 Hz, 1H), 6.68 (d, J = 1.5 Hz, 1H), 6.48 (t, J = 3.5 Hz, 1H), 5.35 (d, J = 53.2 Hz, 1H), 3.96-3.65 (m, 3H), 3.59 (td, J = 10.2, 6.6 Hz, 1H), 2.48-2.26 (m, 2H), 2.08-2.03 (m, 1H), 1.02-0.95 (m, 2H), 0.91 (ddd, J = 10.3, 6.3, 3.9 Hz, 2H) ppm. 297 350 0.49 1H NMR (400 MHz, Acetone-d6) δ 9.14 (d, J = 2.6 Hz, 1H), 8.90 (s, 1H), 8.56 (dd, J = 4.7, 1.2 Hz, 1H), 8.31 (s, 1H), 8.27-8.15 (m, 1H), 7.56 (dd, J = 8.3, 4.7 Hz, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.38 (s, 1H), 3.30-3.09 (m, 4H), 2.62-2.41 (m, 4H), 2.27 (d, J = 5.6 Hz, 6H) ppm. 298 426.28 0.82 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.17 (s, 1H), 7.60 (dd, J = 8.7, 2.2 Hz, 2H), 7.31-7.15 (m, 3H), 6.60 (s, 1H), 6.44-6.34 (m, 1H), 4.89 (d, J = 3.0 Hz, 2H), 4.74 (d, J = 3.5 Hz, 2H), 3.82-3.70 (m, 4H), 3.20-3.08 (m, 4H) ppm. 299 414 0.65 1H NMR (300 MHz, Acetone-d6) δ 8.82 (s, 1H), 8.25 (s, 1H), 7.87 (ddd, J = 11.8, 7.0, 2.6 Hz, 1H), 7.79-7.63 (m, 1H), 7.53 (dt, J = 10.2, 8.8 Hz, 1H), 7.31 (t, J = 2.0 Hz, 1H), 6.95 (s, 1H), 6.38 (s, 1H), 3.77 (d, J = 12.4 Hz, 2H), 3.29 (s, 3H), 3.25 (d, J = 6.1 Hz, 2H), 2.72 (td, J = 12.3, 2.4 Hz, 2H), 2.27 (s, 3H), 1.87-1.68 (m, 3H), 1.37 (ddd, J = 14.9, 12.0, 3.8 Hz, 2H) ppm. 300 378 0.77 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J = 11.6 Hz, 1H), 8.92 (d, J = 5.0 Hz, 1H), 8.66-8.50 (m, 1H), 8.39 (s, 1H), 7.27 (dd, J = 21.0, 9.5 Hz, 3H), 6.93 (d, J = 21.7 Hz, 1H), 6.71 (d, J = 7.0 Hz, 1H), 4.77 (dd, J = 37.1, 12.4 Hz, 1H), 3.90 (t, J = 12.6 Hz, 1H), 3.12 (dd, J = 26.0, 13.6 Hz, 1H), 2.80-2.62 (m, 1H), 2.58 (t, J = 11.9 Hz, 1H), 2.38 (d, J = 9.0 Hz, 3H), 2.14 (d, J = 10.4 Hz, 4H), 2.00-1.49 (m, 4H) ppm. 301 398.26 0.6 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.07 (s, 1H), 7.97 (ddd, J = 11.8, 7.0, 2.5 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.69-7.60 (m, 1H), 7.59 (s, 1H), 7.23 (s, 1H), 7.23 (s, 1H), 6.64 (s, 1H), 4.59 (t, J = 6.6 Hz, 2H), 4.45-4.40 (m, 2H), 3.81-3.73 (m, 1H), 3.68-3.54 (m, 3H), 3.25-3.13 (m, 2H), 2.27 (s, 3H) ppm. 302 433.39 0.58 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.90 (d, J = 0.9 Hz, 1H), 7.57 (s, 1H), 7.05-6.94 (m, 2H), 6.81 (s, 1H), 6.38 (s, 1H), 4.71 (dt, J = 16.5, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.38-3.24 (m, 4H), 2.64 (s, 3H), 2.59-2.49 (m, 4H), 1.96-1.85 (m, 1H), 1.08-0.91 (m, 2H), 0.82-0.71 (m, 2H) ppm. 303 489.1 0.64 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.77-7.66 (m, 2H), 7.43-7.32 (m, 2H), 7.11 (t, J = 2.0 Hz, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 6.46 (s, 1H), 4.79-4.63 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.37-3.24 (m, 4H), 2.72-2.57 (m, 2H), 2.56-2.46 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 304 428.44 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.20 (s, 1H), 7.63 (d, J = 6.7 Hz, 2H), 7.27 (td, J = 9.3, 2.2 Hz, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 6.33 (s, 2H), 5.09 (d, J = 19.2 Hz, 1H), 4.67 (d, J = 49.7 Hz, 3H), 4.16-3.92 (m, 2H), 3.90-3.59 (m, 3H), 3.35 (ddd, J = 46.7, 32.3, 22.1 Hz, 2H), 2.30 (d, J = 14.1 Hz, 4H) ppm. 305 362.38 0.75 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.73-7.65 (m, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.40-7.33 (m, 1H), 7.11 (t, J = 2.1 Hz, 1H), 6.73 (dd, J = 9.9, 8.3 Hz, 2H), 6.33 (d, J = 1.5 Hz, 1H), 3.97-3.81 (m, 4H), 3.27-3.17 (m, 4H), 1.90 (ddd, J = 16.9, 8.5, 5.1 Hz, 1H), 1.01-0.90 (m, 2H), 0.75 (dt, J = 6.7, 4.6 Hz, 2H) ppm. 306 364 0.7 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.06 (s, 1H), 7.84 (dd, J = 5.4, 3.3 Hz, 2H), 7.61-7.46 (m, 2H), 7.33 (dd, J = 19.9, 13.5 Hz, 2H), 6.81 (d, J = 5.3 Hz, 1H), 6.29 (d, J = 16.5 Hz, 1H), 4.07 (dd, J = 6.2, 2.8 Hz, 1H), 3.81-3.65 (m, 1H), 3.54 (d, J = 11.8 Hz, 1H), 3.16 (dd, J = 11.9, 2.8 Hz, 1H), 2.85 (dd, J = 11.7, 6.0 Hz, 1H), 2.25 (d, J = 23.1 Hz, 4H), 1.20 (dd, J = 22.3, 6.3 Hz, 6H) ppm. 307 355.17 0.66 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.51 (d, J = 3.4 Hz, 1H), 8.40 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.05 (td, J = 7.9, 1.8 Hz, 1H), 7.43 (dd, J = 7.0, 5.2 Hz, 1H), 7.13 (s, 1H), 4.05 (dd, J = 8.2, 3.8 Hz, 4H), 3.52-3.44 (m, 4H), 2.29 (d, J = 1.8 Hz, 3H) ppm. 308 334 0.59 1H NMR (400 MHz, Acetone-d6) δ 8.78 (s, 1H), 8.24 (s, 1H), 7.87 (dd, J = 8.6, 1.1 Hz, 2H), 7.54 (dd, J = 8.4, 7.6 Hz, 2H), 7.47 (s, 1H), 7.43 (s, 1H), 7.35 (t, J = 7.4 Hz, 1H), 3.19 (d, J = 12.0 Hz, 2H), 2.77 (dd, J = 12.0, 9.9 Hz, 2H), 2.61 (t, J = 11.9 Hz, 1H), 2.31 (s, 3H), 1.82 (d, J = 12.5 Hz, 2H), 1.70 (ddd, J = 25.1, 12.5, 3.9 Hz, 2H) ppm. 309 391.45 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.06 (d, J = 10.2 Hz, 2H), 7.97-7.76 (m, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 6.90 (s, 1H), 6.55 (s, 1H), 5.92 (s, 1H), 5.59 (d, J = 6.4 Hz, 1H), 4.68-4.52 (m, 2H), 4.46 (dd, J = 12.2, 6.2 Hz, 2H), 3.88 (s, 1H), 3.59 (s, 1H), 2.83 (s, 1H), 2.59 (s, 1H), 2.38 (s, 2H), 2.32-2.17 (m, 1H), 2.14 (s, 3H), 1.67 (d, J = 6.3 Hz, 1H) ppm. 310 443.32 0.61 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.16 (s, 1H), 7.59 (dd, J = 8.5, 2.1 Hz, 2H), 7.26 (dd, J = 10.4, 8.2 Hz, 1H), 6.83 (d, J = 2.0 Hz, 2H), 6.06 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.72 (s, 3H), 3.50-3.39 (m, 1H), 3.20-3.11 (m, 4H), 2.44-2.37 (m, 4H) ppm. 311 459.54 0.64 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.25 (dd, J = 7.7, 2.0 Hz, 2H), 7.07 (s, 1H), 6.79 (dd, J = 9.0, 5.5 Hz, 3H), 6.41 (s, 1H), 3.72 (d, J = 11.1 Hz, 1H), 3.52 (d, J = 10.6 Hz, 1H), 3.26 (t, J = 4.8 Hz, 4H), 3.02 (dd, J = 11.0, 5.0 Hz, 2H), 2.83-2.68 (m, 2H), 2.64 (d, J = 3.0 Hz, 2H), 2.35 (s, 3H), 1.14 (s, 3H) ppm. 312 421.28 0.57 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.39 (s, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 6.44 (s, 1H), 4.72 (dt, J = 15.5, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.37-3.25 (m, 4H), 2.71 (s, 3H), 2.59 (s, 3H), 2.57-2.48 (m, 4H), 2.36 (s, 3H) ppm. 313 469.34 0.58 19F NMR (282 MHz, DMSO-d6) δ −107.59 (s) ppm. 314 437.3 0.56 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.64 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 5.4 Hz, 1H), 7.08 (t, J = 2.0 Hz, 1H), 6.88 (s, 1H), 6.81 (s, 1H), 6.49 (s, 1H), 4.72 (dq, J = 12.5, 6.4 Hz, 4H), 4.11 (s, 3H), 3.60 (p, J = 6.4 Hz, 1H), 3.38-3.23 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 2.61-2.48 (m, 4H), 1.28 (t, J = 7.4, Hz, 3H) ppm. 315 401.35 0.89 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.74-7.66 (m, 2H), 7.58-7.48 (m, 4H), 7.42-7.34 (m, 1H), 7.06 (t, J = 1.5 Hz, 1H), 6.79 (s, 1H), 6.20 (tt, J = 2.9, 1.5 Hz, 2H), 4.37 (q, J = 2.8 Hz, 4H), 3.98 (t, J = 5.5 Hz, 4H), 2.65-2.52 (m, 4H) ppm. 316 334 0.6 1H NMR (300 MHz, Acetone-d6) δ 8.79 (s, 1H), 7.89 (t, J = 1.6 Hz, 1H), 7.88-7.83 (m, 1H), 7.61-7.50 (m, 2H), 7.48 (s, 1H), 7.41 (s, 1H), 7.39-7.31 (m, 1H), 6.62 (s, 1H), 3.05 (dd, J = 20.8, 10.4 Hz, 2H), 2.78-2.51 (m, 6H), 2.31 (s, 3H), 1.96 (d, J = 12.5 Hz, 1H), 1.76-1.50 (m, 3H) ppm. 317 385 0.61 1H NMR (400 MHz, Acetone-d6) δ 8.82 (s, 1H), 8.27 (s, 1H), 7.87 (ddd, J = 11.7, 7.0, 2.6 Hz, 1H), 7.79-7.66 (m, 1H), 7.53 (dt, J = 10.2, 8.8 Hz, 1H), 7.29 (t, J = 1.9 Hz, 1H), 6.98 (s, 1H), 6.38 (s, 1H), 3.24-3.12 (m, 4H), 2.58-2.41 (m, 4H), 2.27 (d, J = 3.5 Hz, 6H) ppm. 318 536.22 0.62 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 6.70 (s, 2H), 6.63 (t, J = 4.7 Hz, 2H), 6.41 (s, 1H), 6.20 (d, J = 11.7 Hz, 1H), 4.79-4.66 (m, 4H), 3.59 (dt, J = 12.6, 6.3 Hz, 1H), 3.53-3.35 (m, 3H), 3.35-3.23 (m, 4H), 2.60-2.51 (m, 4H), 2.49-2.38 (m, 1H), 2.33 (s, 3H), 2.17-1.92 (m, 2H), 1.33 (d, J = 8.0 Hz, 6H) ppm. 319 408.2 0.63 1H NMR (300 MHz, CD3OD) δ 8.92 (s, 1H), 7.92-7.71 (m, 3H), 7.69-7.50 (m, 3H), 7.42 (t, J = 7.5 Hz, 1H), 3.85 (t, J = 4.8 Hz, 8H), 3.43 (t, J = 4.8 Hz, 8H) ppm. 320 339.47 0.71 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.30-9.24 (m, 1H), 9.11 (s, 1H), 8.45 (d, J = 10.5 Hz, 1H), 7.76 (s, 1H), 7.10 (s, 1H), 6.64 (d, J = 72.9 Hz, 1H), 3.52 (s, 3H), 2.46 (s, 1H), 2.30 (s, 2H), 2.09 (d, J = 13.7 Hz, 4H) ppm. 321 376.08 2.96 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.78 (d, J = 2.3 Hz, 1H), 7.90 (td, J = 8.9, 5.9 Hz, 1H), 7.64 (ddd, J = 11.6, 8.9, 2.8 Hz, 1H), 7.33 (t, J = 8.6 Hz, 1H), 7.01 (d, J = 1.9 Hz, 2H), 6.33 (t, J = 19.4 Hz, 1H), 3.91-3.71 (m, 4H), 3.15-3.07 (m, 4H) ppm. 322 473.13 0.64 1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.88-7.71 (m, 4H), 7.13 (d, J = 1.9 Hz, 1H), 6.87 (s, 1H), 6.79 (s, 1H), 6.47 (s, 1H), 4.81-4.62 (m, 4H), 3.69-3.51 (m, 1H), 3.39-3.25 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 2.57-2.48 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 323 423.3 0.62 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.79 (s, 1H), 6.60 (s, 1H), 6.42 (s, 1H), 4.80-4.62 (m, 4H), 3.67-3.47 (m, 1H), 3.39-3.22 (m, 4H), 2.61-2.49 (m, 4H), 2.45 (s, 3H), 2.35 (s, 3H) ppm. 324 455 0.62 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.33-7.20 (m, 4H), 7.12 (s, 1H), 6.78 (tt, J = 8.7, 2.3 Hz, 1H), 6.73 (s, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 3.81 (d, J = 12.5 Hz, 2H), 3.77-3.67 (m, 4H), 2.78 (dd, J = 12.2, 10.2 Hz, 2H), 2.67-2.55 (m, 4H), 2.37 (t, J = 7.4 Hz, 1H), 2.32 (s, 3H), 1.95 (d, J = 12.6 Hz, 2H), 1.75-1.61 (m, 2H) ppm. 325 416.27 0.79 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.17 (s, 1H), 7.66-7.55 (m, 2H), 7.30-7.20 (m, 2H), 6.82 (s, 1H), 6.33 (s, 1H), 3.94 (d, J = 11.5 Hz, 1H), 3.77-3.38 (m, 7H), 3.29 (s, 3H), 2.68 (td, J = 11.7, 3.3 Hz, 1H), 2.23 (s, 3H) ppm. 326 377.37 0.63 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.68 (ddd, J = 17.3, 9.2, 7.1 Hz, 2H), 7.59-7.46 (m, 2H), 7.43-7.32 (m, 1H), 7.12 (d, J = 1.9 Hz, 1H), 6.82 (s, 1H), 6.60 (s, 1H), 6.42 (s, 1H), 3.35-3.22 (m, 4H), 2.82-2.61 (m, 5H), 2.35 (s, 3H), 1.13 (d, J = 6.5 Hz, 6H) ppm. 327 397.26 0.66 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.58 (ddd, J = 10.8, 6.8, 2.5 Hz, 1H), 7.37 (dddd, J = 20.3, 12.3, 7.4, 2.2 Hz, 2H), 6.92 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 3.54 (s, 4H), 1.90 (ddd, J = 12.9, 8.1, 4.8 Hz, 1H), 1.65 (s, 6H), 1.09-0.99 (m, 2H), 0.86 (ddd, J = 10.1, 6.4, 3.7 Hz, 2H) ppm. 328 384 0.64 1H NMR (300 MHz, Acetone-d6) δ 8.94 (s, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.37 (s, 1H), 7.02 (dd, J = 10.2, 8.0 Hz, 1H), 6.67 (s, 1H), 2.97-2.64 (m, 5H), 2.32 (s, 3H), 2.23 (s, 3H), 1.92 (ddd, J = 16.2, 13.9, 6.8 Hz, 4H), 1.72 (ddd, J = 16.6, 12.4, 8.4 Hz, 2H), 1.44 (ddd, J = 24.4, 12.3, 5.0 Hz, 1H) ppm. 329 428.49 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.11 (s, 1H), 7.44 (dd, J = 8.8, 1.8 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 6.34 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.55-3.40 (m, 1H), 3.25-3.03 (m, 3H), 2.49-2.36 (m, 7H), 2.24 (s, 3H) ppm. 330 405.54 0.65 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.74-7.66 (m, 2H), 7.55-7.47 (m, 2H), 7.39-7.32 (m, 1H), 7.16 (t, J = 2.1 Hz, 1H), 6.85 (s, 1H), 6.67 (s, 1H), 6.44 (s, 1H), 4.78-4.65 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.38-3.26 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.58-2.41 (m, 4H), 1.64 (s, 6H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 331 428.29 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.18 (s, 1H), 7.64 (dd, J = 8.6, 2.2 Hz, 2H), 7.32-7.20 (m, 1H), 6.97 (s, 1H), 6.17 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.52 (m, 4H), 3.47-3.37 (m, 1H), 2.33 (m, 4H), 2.23 (s, 3H) ppm. 332 401.18 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.66 (d, J = 18.6 Hz, 1H), 9.20 (s, 1H), 7.69-7.55 (m, 2H), 7.26 (dd, J = 10.5, 8.2 Hz, 1H), 6.74 (d, J = 1.6 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 5.38 (dd, J = 49.3, 17.3 Hz, 1H), 3.74-3.45 (m, 3H), 3.37 (d, J = 7.8 Hz, 1H), 2.25 (s, 2H), 1.85 (s, 1H), 0.89 (d, J = 4.7 Hz, 2H), 0.79 (d, J = 8.1 Hz, 2H) ppm. 333 348 0.6 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.68 (dd, J = 8.6, 1.0 Hz, 2H), 7.50 (dd, J = 10.7, 5.2 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 6.68 (s, 1H), 6.62 (s, 1H), 3.05 (d, J = 10.2 Hz, 2H), 2.48 (s, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 2.16 (s, 2H), 1.90 (s, 3H) ppm. 334 405.49 0.58 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 2H), 7.91-7.76 (m, 2H), 7.52 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.00 (s, 1H), 6.45 (s, 1H), 5.94 (s, 1H), 5.27 (d, J = 7.6 Hz, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 3.47-3.35 (m, 1H), 3.19 (s, 1H), 2.70 (t, J = 11.4 Hz, 2H), 2.13 (s, 3H), 2.03-1.77 (m, 4H), 1.41 (dd, J = 20.6, 10.7 Hz, 2H) ppm. 335 356.3 0.89 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.74-7.64 (m, 2H), 7.59-7.47 (m, 2H), 7.39 (dt, J = 9.2, 4.3 Hz, 1H), 7.10 (d, J = 1.8 Hz, 2H), 6.72 (s, 1H), 6.53 (t, J = 1.9 Hz, 1H), 3.94-3.82 (m, 4H), 3.28-3.17 (m, 4H) ppm. 336 324 0.51 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.08 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 11.7 Hz, 1H), 6.70 (s, 1H), 5.86 (d, J = 12.3 Hz, 1H), 3.22 (t, J = 6.4 Hz, 4H), 1.96 (t, J = 6.5 Hz, 4H) ppm. 337 389 0.61 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.19 (s, 1H), 9.06 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 6.74 (s, 1H), 6.16 (s, 1H), 3.89-3.67 (m, 2H), 3.62-3.37 (m, 4H), 3.36-3.18 (m, 1H), 2.96 (d, J = 4.0 Hz, 1H), 2.23 (s, 3H), 1.29-1.05 (m, 2H), 0.83 (t, J = 11.5 Hz, 2H) ppm. 338 437.12 0.62 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 7.4, 1.7 Hz, 1H), 7.21 (t, J = 2.0 Hz, 1H), 7.15 (dd, J = 11.6, 8.4 Hz, 1H), 7.11-7.06 (m, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.45 (s, 1H), 4.71 (dt, J = 14.4, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.37-3.26 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.57-2.48 (m, 4H), 2.41 (s, 3H), 1.29 (t, J = 10.7, 4.5 Hz, 3H) ppm. 339 436.31 0.57 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 13.9 Hz, 1H), 6.73 (s, 1H), 6.65 (s, 1H), 6.37 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 3.65-3.51 (m, 1H), 3.39-3.22 (m, 4H), 2.61-2.47 (m, 4H), 1.90 (dd, J = 8.9, 4.2 Hz, 1H), 0.97 (dd, J = 12.7, 6.4 Hz, 2H), 0.80-0.65 (m, 2H) ppm. 340 374 0.64 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.79-7.60 (m, 2H), 7.50 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.16 (s, 1H), 6.67 (s, 2H), 3.16 (dd, J = 29.4, 10.9 Hz, 2H), 2.75 (ddd, J = 11.7, 8.2, 3.8 Hz, 1H), 2.35 (s, 3H), 2.31-2.07 (m, 2H), 1.95 (d, J = 12.3 Hz, 1H), 1.87-1.38 (m, 5H) ppm. 341 407 0.61 1H NMR (400 MHz, CDCl3) δ 9.17 (d, J = 1.3 Hz, 1H), 8.90 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 8.38 (dd, J = 2.5, 1.5 Hz, 1H), 6.86 (s, 1H), 6.72 (t, J = 2.0 Hz, 1H), 6.68 (s, 1H), 5.99 (s, 1H), 4.02 (t, J = 7.0 Hz, 2H), 3.85-3.67 (m, 6H), 3.36 (dd, J = 11.6, 6.0 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.47 (s, 4H), 1.26 (t, J = 7.6 Hz, 4H) ppm. 342 406.53 0.53 1H NMR (300 MHz, CDCl3) δ 8.94 (d, J = 2.2 Hz, 1H), 8.66-8.48 (m, 1H), 8.28 (s, 1H), 8.05-7.89 (m, 1H), 7.48-7.29 (m, 1H), 6.83 (dt, J = 3.8, 2.1 Hz, 1H), 6.55 (s, 1H), 6.45 (s, 1H), 6.04 (d, J = 19.5 Hz, 1H), 4.58 (p, J = 6.4 Hz, 4H), 3.50-3.41 (m, 1H), 3.36-3.23 (m, 1H), 2.66 (d, J = 11.7 Hz, 2H), 2.20 (s, 3H), 2.09 (dd, J = 14.0, 11.3 Hz, 2H), 2.01-1.88 (m, 2H), 1.49-1.38 (m, 2H) ppm. 343 390 3.07 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H), 7.87 (dt, J = 8.9, 4.5 Hz, 1H), 7.64 (td, J = 8.9, 4.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 6.73 (d, J = 11.3 Hz, 1H), 6.11 (d, J = 13.0 Hz, 1H), 3.72 (t, J = 4.7 Hz, 2H), 3.56 (dd, J = 11.0, 5.4 Hz, 6H), 2.00-1.83 (m, 2H) ppm. 344 490.53 0.64 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.60 (t, J = 2.0 Hz, 1H), 7.45 (t, J = 1.6 Hz, 1H), 7.39 (s, 1H), 7.28-7.21 (m, 2H), 7.10-7.03 (m, 1H), 6.83 (tt, J = 8.6, 2.2 Hz, 1H), 4.72 (dt, J = 12.4, 6.4 Hz, 4H), 3.68-3.54 (m, 1H), 3.48-3.33 (m, 4H), 3.10 (s, 3H), 2.62-2.47 (m, 4H) ppm. 345 417.09 0.76 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.15-9.01 (m, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.6, 2.5 Hz, 1H), 7.12 (t, J = 6.0 Hz, 2H), 6.85 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.72-3.67 (m, 4H), 3.43-3.36 (m, 4H) ppm. 346 436.18 0.95 1H NMR (300 MHz, CD3OD) δ 8.61 (s, 1H), 7.42-7.31 (m, 2H), 7.25 (dd, J = 17.5, 1.8 Hz, 2H), 6.89-6.75 (m, 1H), 6.68 (s, 1H), 3.97-3.80 (m, 4H), 3.29-3.12 (m, 4H) ppm. 347 403 223 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.58 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 7.90 (td, J = 8.9, 5.9 Hz, 1H), 7.64 (ddd, J = 11.7, 9.0, 2.8 Hz, 1H), 7.34 (t, J = 8.5 Hz, 1H), 6.81 (d, J = 11.8 Hz, 1H), 6.74 (s, 1H), 5.98 (d, J = 11.9 Hz, 1H), 3.98 (d, J = 7.3 Hz, 1H), 3.61 (t, J = 9.0 Hz, 1H), 3.57-3.49 (m, 1H), 3.45 (d, J = 5.9 Hz, 1H), 3.25 (dd, J = 16.9, 8.2 Hz, 1H), 2.80 (t, J = 4.3 Hz, 6H), 2.41 (s, 1H), 2.35-2.25 (m, 1H) ppm. 348 411.39 0.66 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.75-7.66 (m, 2H), 7.58-7.47 (m, 2H), 7.38 (ddd, J = 8.7, 4.6, 1.2 Hz, 2H), 7.12 (d, J = 22.4 Hz, 2H), 6.81-6.40 (m, 2H), 3.35-3.20 (m, 4H), 2.89-2.75 (m, 4H), 1.77-1.67 (m, 1H), 0.62-0.41 (m, 4H) ppm. 349 427.21 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.18 (s, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 2H), 7.34 (s, 1H), 7.31-7.17 (m, 1H), 6.82 (s, 1H), 6.38 (s, 1H), 4.77 (d, J = 6.7 Hz, 2H), 4.21 (d, J = 6.8 Hz, 2H), 3.05 (m, 2H), 2.63-2.52 (m, 4H), 2.49 (s, 3H), 2.24 (s, 3H) ppm. 350 497.2 0.44 1H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 7.96-7.73 (m, 1H), 7.63 (d, J = 6.3 Hz, 2H), 7.35 (s, 1H), 7.00 (t, J = 9.2 Hz, 2H), 4.30-4.13 (m, 2H), 4.00 (s, 4H), 3.74 (dd, J = 13.9, 8.8 Hz, 4H), 2.43 (s, 3H), 1.31 (t, J = 7.1 Hz, 4H) ppm. 351 343 0.63 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 9.17 (s, 1H), 7.76 (dd, J = 14.8, 5.0 Hz, 2H), 7.63 (dd, J = 14.5, 8.1 Hz, 1H), 7.27-7.13 (m, 1H), 6.79 (d, J = 11.8 Hz, 1H), 6.69 (s, 1H), 5.87 (d, J = 11.4 Hz, 1H), 4.31 (dd, J = 14.1, 6.7 Hz, 1H), 4.23 (d, J = 7.0 Hz, 2H), 3.84 (dd, J = 16.4, 7.2 Hz, 2H) ppm. 352 467.28 0.82 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.25 (dd, J = 7.8, 2.2 Hz, 2H), 7.19-6.97 (m, 1H), 6.91-6.72 (m, 3H), 6.42 (s, 1H), 4.01-3.85 (m, 2H), 3.85-3.70 (m, 2H), 3.43-3.19 (m, 4H), 2.36 (s, 3H) ppm. 353 463.32 0.55 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.92 (d, J = 1.1 Hz, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.18 (t, J = 2.1 Hz, 1H), 6.87 (s, 1H), 6.71 (s, 1H), 6.41 (s, 1H), 4.72 (dq, J = 12.6, 6.4 Hz, 4H), 4.63 (s, 2H), 4.14 (q, J = 7.1 Hz, 1H), 3.58 (s, 3H), 3.39-3.25 (m, 4H), 2.61-2.48 (m, 4H), 1.90 (tt, J = 8.4, 5.1 Hz, 1H), 1.05-0.89 (m, 2H), 0.87-0.70 (m, 2H) ppm. 354 423.28 0.58 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.04 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.6, 2.4 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.76 (s, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.73-3.62 (m, 4H), 3.37-3.33 (m, 4H), 1.83 (ddd, J = 13.2, 8.3, 5.1 Hz, 1H), 0.85 (dd, J = 7.2, 4.8 Hz, 2H), 0.82-0.73 (m, 2H) ppm. 355 358.22 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.16 (s, 1H), 7.67-7.52 (m, 2H), 7.30-7.17 (m, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 5.81 (s, 1H), 5.60 (d, J = 6.7 Hz, 1H), 4.56 (dd, J = 11.6, 5.3 Hz, 1H), 4.05 (t, J = 7.0 Hz, 2H), 3.48 (dd, J = 7.5, 5.2 Hz, 2H), 2.19 (s, 3H) ppm. 356 388.17 2.65 357 392.18 0.85 1H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.26 (s, 1H), 9.03 (d, J = 1.3 Hz, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.60 (dd, J = 2.5, 1.4 Hz, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 6.77 (s, 1H), 3.82-3.72 (m, 4H), 3.23-3.15 (m, 4H) ppm. 358 376.38 0.59 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.69-7.56 (m, 2H), 7.42 (dd, J = 10.7, 5.1 Hz, 2H), 7.34-7.23 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 19.1 Hz, 1H), 6.57 (s, 1H), 6.31 (d, J = 18.5 Hz, 1H), 4.02-3.68 (m, 4H), 3.18-2.98 (m, 1H), 2.85-2.68 (m, 1H), 2.67-2.52 (m, 1H), 2.25 (s, 3H), 2.18-1.88 (m, 2H), 1.84-1.53 (m, 3H) ppm. 359 455.29 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.16 (s, 1H), 7.72-7.49 (m, 2H), 7.25 (dd, J = 10.4, 8.2 Hz, 1H), 7.10 (s, 1H), 7.03 (s, 1H), 6.38 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.56-3.39 (m, 1H), 3.16 (s, 4H), 2.79 (dt, J = 14.2, 7.0 Hz, 1H), 2.42 (d, J = 4.6 Hz, 4H), 1.21 (t, J = 6.7 Hz, 6H) ppm. 360 399.25 0.79 1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.15 (s, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 2H), 7.28-7.17 (m, 1H), 7.13 (s, 1H), 6.88 (s, 1H), 6.34 (s, 1H), 3.74 (s, 2H), 3.52-3.39 (m, 4H), 2.90 (s, 3H), 2.24 (s, 3H) ppm. 361 473.37 0.66 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 7.61 (t, J = 2.0 Hz, 1H), 7.57-7.34 (m, 5H), 7.14-7.00 (m, 2H), 4.72 (dq, J = 12.4, 6.4 Hz, 4H), 3.68-3.52 (m, 1H), 3.50-3.26 (m, 4H), 3.10 (s, 3H), 2.64-2.43 (m, 4H) ppm. 362 385 0.62 1H NMR (300 MHz, Acetone-d6) δ 8.93 (s, 1H), 8.36 (s, 1H), 7.58 (dd, J = 8.7, 2.3 Hz, 2H), 7.40 (s, 1H), 7.02 (ddd, J = 9.1, 5.7, 2.3 Hz, 1H), 6.90 (s, 1H), 6.39 (s, 1H), 3.59 (t, J = 10.4 Hz, 2H), 3.12-2.52 (m, 4H-water peak), 2.37-2.22 (m, 4H), 1.11 (d, J = 6.3 Hz, 3H) ppm. 363 307.18 0.77 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.08 (s, 1H), 7.85 (dd, J = 8.6, 1.1 Hz, 2H), 7.56 (dd, J = 10.7, 5.3 Hz, 3H), 7.40-7.29 (m, 2H), 6.71 (s, 1H), 4.95 (dd, J = 8.4, 5.8 Hz, 2H), 4.62 (dd, J = 6.7, 5.8 Hz, 2H), 4.23-4.11 (m, 1H), 2.28 (d, J = 6.4 Hz, 3H) ppm. 364 437.3 0.53 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.93 (d, J = 1.1 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 7.33 (s, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 6.45 (s, 1H), 4.72 (p, J = 6.4 Hz, 4H), 4.64 (d, J = 8.4 Hz, 2H), 3.57 (s, 3H), 3.36 (dd, J = 13.1, 8.2 Hz, 4H), 2.61-2.49 (m, 4H) ppm. 365 386.19 0.52 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.21 (s, 1H), 7.70-7.53 (m, 2H), 7.28 (tt, J = 9.3, 2.3 Hz, 1H), 6.94 (s, 1H), 6.72 (s, 1H), 3.50-3.37 (m, 4H), 2.44-2.33 (m, 4H), 2.25 (s, 3H), 2.22 (s, 3H). 366 390.24 4.33 1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.88-7.79 (m, 2H), 7.56 (m, 4H), 7.38 (t, J = 7.4 Hz, 1H), 6.81 (s, 1H), 3.80 (m, 4H), 3.28-3.18 (m, 4H) ppm. 367 370.17 0.76 1H NMR (300 MHz, CD3OD) δ 8.83 (s, 1H), 7.90-7.72 (m, 2H), 7.66-7.48 (m, 2H), 7.46-7.33 (m, 1H), 7.13-6.89 (m, 2H), 4.41 (d, J = 11.5 Hz, 2H), 3.73-3.48 (m, 2H), 3.21 (q, J = 10.7, 9.0 Hz, 4H), 2.96 (s, 3H) ppm. 368 451.28 0.81 1H NMR (300 MHz, CDCl3) δ 9.19 (d, J = 1.3 Hz, 1H), 8.93 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.41 (dd, J = 2.5, 1.5 Hz, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 6.48 (s, 1H), 3.70-3.52 (m, 4H), 3.32-3.15 (m, 4H), 2.66 (q, J = 7.6 Hz, 2H), 1.52 (s, 9H), 1.29 (t, J = 7.6 Hz, 3H) ppm. 369 375.43 0.64 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.22 (d, J = 16.0 Hz, 1H), 9.15-9.00 (m, 1H), 7.96-7.81 (m, 2H), 7.65-7.47 (m, 2H), 7.36 (q, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.20-6.11 (m, 1H), 4.12 (d, J = 6.1 Hz, 1H), 3.89 (d, J = 11.9 Hz, 1H), 3.67-3.49 (m, 1H), 3.43-3.08 (m, 5H), 2.85 (dd, J = 18.9, 4.9 Hz, 3H), 2.43 (d, J = 7.1 Hz, 1H), 2.23 (s, 3H), 2.23 (s, 3H), 1.78 (dd, J = 14.9, 7.9 Hz, 1H) ppm. 370 413.25 0.28 1H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 8.00 (s, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.36 (s, 1H), 7.10-6.91 (m, 2H), 4.04 (s, 4H), 3.76 (d, J = 24.8 Hz, 4H), 2.22 (s, 3H) ppm. 371 359.41 0.9 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.26 (s, 1H), 9.04 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 7.15 (s, 1H), 7.06 (d, J = 11.4 Hz, 1H), 6.45 (d, J = 11.8 Hz, 1H), 3.80 (s, 4H), 3.18 (s, 4H) ppm. 372 334.12 0.68 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.68-7.48 (m, 2H), 7.36-7.28 (m, 2H), 6.81 (s, 1H), 6.62 (s, 2H), 6.07 (s, 1H), 3.51-3.27 (m, 4H), 2.42 (s, 3H), 2.40-2.27 (m, 3H), 2.12-1.93 (m, 4H) ppm. 373 496.22 0.61 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 6.78 (s, 2H), 6.67 (dt, J = 9.2, 1.9 Hz, 1H), 6.44-6.31 (m, 2H), 4.71 (dt, J = 14.8, 6.4 Hz, 4H), 3.64-3.51 (m, 5H), 3.38 (s, 3H), 3.34-3.26 (m, 4H), 3.06 (s, 3H), 2.57-2.46 (m, 4H), 2.33 (s, 3H) ppm. 374 372.08 2.5 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.18 (s, 1H), 7.67 (d, J = 6.9 Hz, 2H), 7.42 (s, 1H), 7.34-7.15 (m, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 3.77 (d, J = 61.3 Hz, 4H), 3.20 (d, J = 28.0 Hz, 4H), 2.30 (d, J = 23.2 Hz, 3H) ppm. 375 423.45 0.66 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.54-7.40 (m, 3H), 7.12 (s, 1H), 7.10-6.99 (m, 1H), 6.81 (s, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.42-3.14 (m, 4H), 2.68-2.46 (m, 4H), 2.35 (s, 3H), 1.44 (s, 3H) ppm. 376 433.44 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.07 (s, 1H), 7.96-7.74 (m, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 6.48 (s, 1H), 4.57 (q, J = 6.2 Hz, 2H), 4.47 (dt, J = 9.0, 6.1 Hz, 2H), 3.56-3.39 (m, 1H), 3.25-3.07 (m, 4H), 2.47-2.41 (m, 3H), 1.28 (s, 8H) ppm. 377 449.32 0.61 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.62 (d, J = 0.6 Hz, 1H), 7.05 (d, J = 0.6 Hz, 1H), 7.03 (t, J = 2.0 Hz, 1H), 6.85 (d, J = 17.5 Hz, 1H), 6.77 (s, 1H), 6.37 (s, 1H), 4.79-4.65 (m, 4H), 4.07 (s, 3H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.24 (m, 4H), 2.59-2.47 (m, 4H), 1.97-1.85 (m, 1H), 1.05-0.91 (m, 2H), 0.81-0.69 (m, 2H) ppm. 378 397.31 0.67 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.20 (s, 1H), 7.70-7.54 (m, 2H), 7.33-7.14 (m, 1H), 6.89 (d, J = 1.4 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 3.49-3.36 (m, 4H), 1.85 (ddd, J = 12.9, 8.1, 4.9 Hz, 1H), 1.55 (dd, J = 15.1, 4.4 Hz, 6H), 0.91-0.73 (m, 4H) ppm. 379 408.25 0.89 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.14 (s, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.64-7.54 (m, 2H), 7.53 (d, J = 1.5 Hz, 1H), 7.22 (tt, J = 10.4, 8.2 Hz, 1H), 6.78 (d, J = 10.2 Hz, 2H), 6.31-6.27 (m, 1H), 5.90 (s, 1H), 5.39 (m, 1H), 4.30 (t, J = 7.4 Hz, 2H), 4.11-4.02 (m, 2H), 2.22 (s, 3H) ppm. 380 340 3.45 1H NMR (400 MHz, Acetone-d6) δ 8.80 (s, 1H), 8.40 (s, 1H), 7.86 (dd, J = 8.6, 1.0 Hz, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 1.8 Hz, 1H), 7.02 (t, J = 2.0 Hz, 1H), 6.13 (t, J = 2.0 Hz, 1H), 3.31 (t, J = 6.6 Hz, 4H). 2.02, (t, J = 6.6. Hz, 4H—under the acetone peak) ppm. 381 351.35 0.56 1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.51 (s, 1H), 9.31 (s, 2H), 9.24 (s, 1H), 9.17 (s, 1H), 7.20 (s, 1H), 6.93 (d, J = 17.4 Hz, 1H), 6.40 (s, 1H), 3.75 (d, J = 10.7 Hz, 2H), 3.50 (d, J = 9.7 Hz, 2H), 3.19-3.10 (m, 4H), 2.79 (t, J = 13.4 Hz, 3H), 2.27 (d, J = 11.9 Hz, 3H) ppm. 382 394.29 0.6 1H NMR (300 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.12 (s, 1H), 7.73 (s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.65-7.54 (m, 1H), 7.52 (s, 1H), 7.18 (dd, J = 13.0, 4.5 Hz, 2H), 6.61 (s, 1H), 4.59 (t, J = 6.5 Hz, 2H), 4.51 (td, J = 6.0, 1.4 Hz, 2H), 3.66 (dd, J = 12.3, 6.2 Hz, 1H), 3.29-3.19 (m, 1H), 2.96 (t, J = 8.4 Hz, 1H), 2.72 (dd, J = 14.9, 8.2 Hz, 1H), 2.61 (dd, J = 14.3, 8.6 Hz, 1H), 2.47-2.38 (m, 1H), 2.32-2.17 (m, 4H), 1.79 (dt, J = 14.5, 8.0 Hz, 1H) ppm. 383 426.51 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.81 (d, J = 2.4 Hz, 1H), 7.69 (ddd, J = 9.2, 6.0, 3.2 Hz, 1H), 7.64-7.48 (m, 1H), 7.41-7.23 (m, 1H), 7.18 (s, 1H), 6.79 (s, 1H), 6.30 (s, 1H), 4.62 (dd, J = 7.8, 5.9 Hz, 2H), 4.37 (t, J = 6.1 Hz, 2H), 3.67 (d, J = 12.3 Hz, 2H), 2.81-2.58 (m, 3H), 2.21 (s, 3H), 1.77 (d, J = 10.1 Hz, 1H), 1.65 (d, J = 13.1 Hz, 2H), 1.14 (dt, J = 11.9, 8.6 Hz, 2H) ppm. 384 442.44 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.07 (s, 1H), 7.92 (ddd, J = 15.9, 9.5, 7.4 Hz, 1H), 7.77-7.63 (m, 2H), 7.25 (s, 1H), 6.88 (s, 1H), 6.28 (s, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4.37-4.18 (m, 1H), 3.53-3.36 (m, 1H), 2.60 (dd, J = 17.1, 11.7 Hz, 2H), 2.21 (d, J = 9.7 Hz, 3H), 2.15-1.90 (m, 4H), 1.78-1.54 (m, 2H) ppm. 385 379 0.49 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.30 (s, 1H), 8.78-8.64 (m, 2H), 7.81 (dd, J = 4.7, 1.6 Hz, 2H), 7.16 (s, 1H), 6.86 (s, 1H), 6.32 (s, 1H), 3.68 (d, J = 12.4 Hz, 2H), 3.34 (s, 1H), 3.25 (s, 3H), 3.19 (dd, J = 11.9, 5.6 Hz, 3H), 2.77-2.59 (m, 2H), 2.23 (s, 3H), 1.74 (d, J = 10.1 Hz, 3H), 1.41-1.20 (m, 2H) ppm. 386 427.41 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.05 (s, 1H), 8.18-7.81 (m, 1H), 7.81-7.53 (m, 2H), 7.13 (s, 1H), 6.88 (s, 1H), 6.31 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.53-4.39 (m, 2H), 3.45 (p, J = 6.2 Hz, 1H), 3.24-3.10 (m, 4H), 2.46-2.37 (m, 4H), 2.23 (s, 3H) ppm. 387 368.21 0.55 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 7.71 (dt, J = 9.1, 2.3 Hz, 1H), 7.00 (s, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.35 (s, 1H), 3.30-3.16 (m, 3H), 2.64-2.47 (m, 3H), 2.31 (s, 2H), 2.26 (s, 3H) ppm. 388 465.38 0.86 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.13-7.05 (m, 2H), 7.00 (dt, J = 9.3, 2.1 Hz, 1H), 6.74 (s, 1H), 6.60 (dt, J = 11.3, 2.3 Hz, 2H), 6.37 (s, 1H), 4.83-4.62 (m, 4H), 3.89 (s, 3H), 3.68-3.48 (m, 1H), 3.40-3.21 (m, 4H), 2.61-2.43 (m, 4H), 1.89 (ddd, J = 13.4, 8.4, 5.1 Hz, 1H), 1.02-0.88 (m, 2H), 0.82-0.64 (m, 2H) ppm. 389 453.28 0.63 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.24 (dd, J = 7.7, 2.0 Hz, 2H), 7.07 (t, J = 2.0 Hz, 1H), 6.85-6.76 (m, 1H), 6.71 (s, 1H), 6.62 (s, 1H), 6.36 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 3.64-3.53 (m, 1H), 3.37-3.25 (m, 4H), 2.58-2.48 (m, 4H), 1.90 (ddd, J = 13.4, 8.4, 5.0 Hz, 1H), 1.01-0.89 (m, 2H), 0.81-0.69 (m, 2H) ppm. 390 438.38 0.5 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.45 (s, 1H), 7.34 (d, J = 9.4 Hz, 1H), 7.17 (s, 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.77 (s, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 3.54 (s, 2H), 3.37-3.22 (m, 4H), 2.67-2.56 (m, 4H), 2.50 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H) ppm. 391 392.49 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.06 (s, 1H), 7.93-7.69 (m, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 6.22 (s, 1H), 4.87 (s, 1H), 4.59 (t, J = 5.7 Hz, 2H), 4.49 (dd, J = 9.3, 5.9 Hz, 2H), 3.73 (s, 1H), 2.95 (s, 1H), 2.73 (s, 2H), 2.52 (s, 1H), 2.39-2.16 (m, 4H), 1.90 (s, 1H) ppm. 392 372.28 0.83 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.51 (s, 1H), 7.77-7.69 (m, 2H), 7.57-7.49 (m, 2H), 7.44-7.33 (m, 2H), 7.27 (s, 1H), 6.63 (dd, J = 64.1, 49.2 Hz, 2H), 3.98-3.83 (m, 4H), 3.31-3.20 (m, 4H) ppm. 393 444.21 0.64 394 358.15 2.96 1H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 40.8 Hz, 1H), 9.13 (d, J = 19.3 Hz, 1H), 7.71 (t, J = 9.6 Hz, 2H), 7.57 (d, J = 37.5 Hz, 1H), 7.18 (d, J = 24.8 Hz, 1H), 7.00 (s, 2H), 6.30 (t, J = 16.7 Hz, 1H), 3.72 (d, J = 25.2 Hz, 4H), 3.12 (s, 4H) ppm. 395 397.24 0.62 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 7.01 (dt, J = 9.3, 2.0 Hz, 1H), 6.75 (s, 1H), 6.66 (s, 1H), 6.60 (dt, J = 10.4, 2.2 Hz, 1H), 6.42 (s, 1H), 3.88 (s, 3H), 3.36-3.22 (m, 4H), 2.67-2.55 (m, 4H), 2.38 (s, 3H), 2.34 (s, 3H) ppm. 396 455.53 0.7 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 3.8 Hz, 1H), 7.25 (dd, J = 7.9, 2.2 Hz, 2H), 7.15 (t, J = 2.0 Hz, 1H), 6.86-6.75 (m, 2H), 6.71 (s, 1H), 6.45 (s, 1H), 4.83-4.62 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.40-3.21 (m, 4H), 2.66-2.46 (m, 6H), 1.69 (dd, J = 15.1, 7.4 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H) ppm. 397 425.19 0.62 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.12 (s, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.2, 1.3 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (s, 1H), 6.84 (s, 1H), 6.31 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.46 (dd, J = 12.4, 6.3 Hz, 1H), 3.22-3.12 (m, 4H), 2.45-2.36 (m, 4H), 2.22 (s, 3H) ppm. 398 417.37 0.68 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.59 (ddd, J = 16.1, 8.6, 6.5 Hz, 2H), 7.48-7.34 (m, 2H), 7.34-7.23 (m, 1H), 7.04 (s, 1H), 6.73 (s, 1H), 6.54 (s, 1H), 6.31 (s, 1H), 3.26-3.11 (m, 4H), 2.97 (q, J = 9.6 Hz, 2H), 2.86-2.68 (m, 4H), 2.25 (s, 3H) ppm. 399 351.31 0.56 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.87 (dd, J = 2.8, 0.9 Hz, 1H), 9.69 (d, J = 8.1 Hz, 1H), 9.51 (s, 1H), 9.47-9.24 (m, 1H), 8.14 (dd, J = 6.0, 2.8 Hz, 1H), 7.19 (s, 1H), 7.00 (s, 1H), 6.45 (s, 1H), 3.76 (d, J = 9.3 Hz, 2H), 3.51 (d, J = 8.1 Hz, 2H), 3.31-3.04 (m, 4H), 2.79 (t, J = 13.9 Hz, 3H), 2.27 (s, 3H) ppm. 400 469.34 0.84 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.39-7.31 (m, 1H), 7.16-7.02 (m, 2H), 6.70 (s, 1H), 6.61 (s, 1H), 6.36 (s, 1H), 4.80-4.62 (m, 4H), 3.67-3.51 (m, 1H), 3.38-3.27 (m, 4H), 2.61-2.50 (m, 4H), 1.97-1.82 (m, 1H), 1.03-0.89 (m, 2H), 0.75 (dt, J = 6.6, 4.6 Hz, 2H) ppm. 401 421.26 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.15 (s, 1H), 8.83 (s, 1H), 8.56 (s, 1H), 7.16 (s, 1H), 6.98 (s, 1H), 6.37 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.54-3.38 (m, 1H), 3.16 (d, J = 4.7 Hz, 4H), 2.70-2.52 (m, 5H), 2.40 (t, J = 13.3 Hz, 4H), 1.19 (t, J = 7.6 Hz, 3H) ppm. 402 391 0.59 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.00 (s, 1H), 6.61 (s, 1H), 6.49 (s, 1H), 6.07 (s, 1H), 4.52 (d, J = 13.6 Hz, 1H), 3.82 (d, J = 13.9 Hz, 1H), 3.63-3.50 (m, 2H), 3.31-3.12 (m, 1H), 2.96-2.76 (m, 1H), 2.27 (s, 3H), 2.19 (d, J = 16.2 Hz, 1H), 2.12 (s, 3H), 1.39 (d, J = 4.9 Hz, 2H) ppm. 403 355.45 0.73 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.37 (d, J = 21.6 Hz, 1H), 8.31 (dd, J = 24.3, 5.5 Hz, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.85 (d, J = 23.0 Hz, 2H), 7.20 (s, 1H), 6.89 (d, J = 29.4 Hz, 1H), 4.03 (s, 4H), 3.37 (d, J = 40.0 Hz, 4H), 2.32 (s, 3H) ppm. 404 308 0.79 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.42 (d, J = 4.2 Hz, 1H), 7.87 (dt, J = 15.3, 4.8 Hz, 2H), 7.53 (s, 1H), 7.24 (d, J = 9.3 Hz, 2H), 6.93 (s, 1H), 6.86 (s, 1H), 5.10 (dd, J = 8.4, 6.0 Hz, 2H), 4.84 (t, J = 6.4 Hz, 2H), 4.36-4.12 (m, 1H), 2.40 (s, 3H) ppm. 405 399.15 0.65 1H NMR (300 MHz, CD3OD) δ 9.03 (s, 1H), 7.67-7.45 (m, 2H), 7.36 (s, 1H), 7.05 (tt, J = 9.0, 2.3 Hz, 1H), 6.64 (s, 1H), 3.88 (dd, J = 6.0, 3.7 Hz, 4H), 3.59 (dd, J = 6.0, 3.7 Hz, 4H), 2.17 (tt, J = 8.3, 5.0 Hz, 1H), 1.36-1.18 (m, 2H), 0.99 (dt, J = 7.2, 4.8 Hz, 2H) ppm. 406 409.45 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.11 (s, 1H), 7.79-7.66 (m, 2H), 7.62-7.52 (m, 1H), 7.24-7.04 (m, 2H), 6.88 (s, 1H), 6.31 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 3.45 (p, J = 6.3 Hz, 1H), 3.27-3.12 (m, 4H), 2.47-2.38 (m, 4H), 2.23 (s, 3H) ppm. 407 398.21 0.61 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.26 (d, J = 2.2 Hz, 2H), 7.17 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.95-6.78 (m, 2H), 4.11 (d, J = 10.9 Hz, 2H), 3.58 (td, J = 11.3, 3.5 Hz, 2H), 2.97-2.79 (m, 1H), 2.03 (td, J = 8.0, 4.0 Hz, 1H), 1.96-1.80 (m, 4H), 1.11-1.02 (m, 2H), 0.97 (ddd, J = 10.3, 6.4, 3.9 Hz, 2H) ppm. 408 426 0.64 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.31 (s, 1H), 7.26 (d, J = 5.6 Hz, 3H), 7.14 (s, 1H), 6.87-6.74 (m, 2H), 6.68 (s, 1H), 4.76-4.58 (m, 4H), 3.50 (p, J = 6.6 Hz, 1H), 2.84 (dd, J = 16.7, 9.1 Hz, 3H), 2.36 (s, 3H), 2.00 (d, J = 12.6 Hz, 1H), 1.95-1.68 (m, 4H), 1.58-1.43 (m, 1H) ppm. 409 325.19 0.82 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.13 (s, 1H), 7.77-7.68 (m, 2H), 7.59 (dt, J = 8.4, 5.5 Hz, 2H), 7.31 (s, 1H), 7.19 (td, J = 8.2, 2.0 Hz, 1H), 6.72 (s, 1H), 4.95 (dd, J = 8.3, 5.8 Hz, 2H), 4.62 (dd, J = 6.6, 5.9 Hz, 2H), 4.26-4.09 (m, 1H), 2.30 (s, 3H) ppm. 410 406.48 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.06 (s, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.9 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.28 (s, 1H), 6.88 (s, 1H), 6.27 (s, 1H), 4.54 (t, J = 6.4 Hz, 2H), 4.44 (t, J = 6.1 Hz, 2H), 4.31 (s, 1H), 3.41 (dd, J = 13.4, 6.3 Hz, 1H), 2.57 (s, 2H), 2.25 (d, J = 14.3 Hz, 3H), 2.14-1.94 (m, 4H), 1.65 (d, J = 8.8 Hz, 2H) ppm. 411 408 0.66 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.46 (dd, J = 5.8, 4.1 Hz, 3H), 7.33 (s, 1H), 7.14 (s, 1H), 7.05 (ddd, J = 10.4, 7.0, 3.4 Hz, 1H), 6.67 (d, J = 5.5 Hz, 2H), 4.75-4.53 (m, 4H), 3.60-3.39 (m, 1H), 2.96-2.73 (m, 3H), 2.36 (s, 3H), 2.00 (d, J = 12.1 Hz, 1H), 1.94-1.60 (m, 5H), 1.50 (dt, J = 12.3, 10.4 Hz, 1H) ppm. 412 439 0.67 1H NMR (300 MHz, Acetone-d6) δ 8.89 (s, 1H), 8.74 (s, 1H), 7.87 (ddd, J = 11.7, 7.0, 2.6 Hz, 1H), 7.79-7.70 (m, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.61-7.50 (m, 2H), 6.80 (s, 1H), 3.37-3.24 (m, 4H), 2.62-2.46 (m, 4H), 2.29 (s, 3H) ppm. 413 445.18 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 7.96 (tt, J = 14.8, 5.6 Hz, 2H), 7.11 (s, 1H), 6.86 (s, 1H), 6.30 (s, 1H), 4.57 (t, J = 6.4 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 3.49-3.39 (m, 1H), 3.13 (s, 4H), 2.40 (s, 4H), 2.21 (s, 3H) ppm. 414 405.3 2.82 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.24 (s, 1H), 7.55-7.33 (m, 4H), 7.16 (s, 1H), 6.92 (s, 1H), 6.42 (s, 1H), 5.13-5.00 (m, 2H), 4.82 (t, J = 7.6 Hz, 2H), 4.27-4.12 (m, 1H), 3.56 (d, J = 4.6 Hz, 4H), 3.25 (s, 4H), 2.36 (d, J = 11.2 Hz, 6H) ppm. 415 467.32 0.65 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.17 (s, 1H), 7.03 (s, 1H), 6.98 (dt, J = 9.3, 2.1 Hz, 1H), 6.76 (s, 1H), 6.61 (s, 1H), 6.57 (dt, J = 10.6, 2.2 Hz, 1H), 6.41 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 4.59 (dt, J = 12.1, 6.1 Hz, 1H), 3.65-3.51 (m, 1H), 3.37-3.26 (m, 4H), 2.60-2.46 (m, 4H), 2.34 (s, 3H), 1.40 (d, J = 6.1 Hz, 6H) ppm. 416 428.28 0.6 1H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.17 (s, 1H), 7.74 (s, 1H), 7.69-7.58 (m, 2H), 7.25 (m, 2H), 6.85 (s, 1H), 5.18 (s, 1H), 4.57 (dd, J = 9.9, 4.3 Hz, 2H), 4.51 (dd, J = 13.1, 6.0 Hz, 2H), 3.82-3.71 (m, 1H), 2.92-2.70 (m, 4H), 2.29 (s, 3H), 2.21-1.97 (m, 2H) ppm. 417 441.24 0.66 1H NMR (300 MHz, CDCl3) δ 8.53 (d, J = 2.4 Hz, 1H), 7.74 (ddd, J = 9.2, 6.1, 3.1 Hz, 1H), 7.28-7.20 (m, 1H), 7.17 (t, J = 2.0 Hz, 1H), 6.98 (ddt, J = 9.2, 6.9, 3.4 Hz, 1H), 6.83 (s, 1H), 6.73 (s, 1H), 6.47 (s, 1H), 4.85-4.60 (m, 4H), 3.70-3.52 (m, 1H), 3.44-3.21 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 2.60-2.38 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 418 407.29 0.61 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.74 (d, J = 5.5 Hz, 1H), 7.52 (d, J = 5.5 Hz, 1H), 7.13 (s, 1H), 7.08 (t, J = 1.9 Hz, 1H), 6.84 (s, 1H), 6.44 (s, 1H), 4.72 (dq, J = 12.6, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.24 (m, 4H), 2.75 (s, 3H), 2.61-2.46 (m, 4H), 2.35 (s, 3H) ppm. 419 377 0.6 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.20 (s, 1H), 7.05 (s, 1H), 6.75 (s, 1H), 6.56 (s, 1H), 3.38-3.19 (m, 1H), 3.12 (dd, J = 11.7, 2.6 Hz, 1H), 2.89 (dd, J = 11.9, 3.0 Hz, 1H), 2.79-2.60 (m, 1H), 2.36 (d, J = 18.0 Hz, 7H), 2.24-2.09 (m, 1H), 1.06 (d, J = 6.2 Hz, 3H), 1.02 (d, J = 6.1 Hz, 3H) ppm. 420 391.23 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.14 (s, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 7.15 (s, 1H), 6.90 (s, 1H), 6.18 (d, J = 83.2 Hz, 1H), 3.19-3.01 (m, 4H), 2.78-2.61 (m, 4H), 2.56 (s, 3H), 2.23 (s, 3H), 1.75-1.56 (m, 1H), 0.56-0.40 (m, 2H), 0.39-0.27 (m, 2H) ppm. 421 453.42 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.15 (s, 1H), 7.72-7.45 (m, 2H), 7.24 (tt, J = 9.3, 2.2 Hz, 1H), 7.21-7.12 (m, 1H), 6.86 (s, 1H), 6.32 (s, 1H), 3.24 (dd, J = 20.4, 10.2 Hz, 2H), 3.18-3.06 (m, 4H), 2.84-2.69 (m, 4H), 2.23 (s, 3H) ppm. 422 429.23 0.32 423 377.41 0.59 424 381.26 0.62 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17 (s, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 6.42 (s, 1H), 3.39-3.25 (m, 4H), 2.65 (s, 4H), 2.44 (d, J = 6.3 Hz, 3H), 2.41 (s, 3H), 2.35 (s, 3H) ppm. 425 441.45 0.68 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 8.0, 2.2 Hz, 2H), 6.79 (tt, J = 8.7, 2.3 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J = 2.2 Hz, 1H), 4.83-4.64 (m, 4H), 3.61 (p, J = 6.3 Hz, 1H), 3.41-3.26 (m, 4H), 2.57 (d, J = 4.3 Hz, 4H), 2.32 (s, 3H), 2.18 (s, 3H) ppm. 426 392.22 0.93 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.25 (dd, J = 7.9, 2.2 Hz, 2H), 7.11-7.04 (m, 2H), 6.82 (tt, J = 8.7, 2.3 Hz, 1H), 6.69 (s, 1H), 6.55 (t, J = 1.9 Hz, 1H), 3.97-3.81 (m, 4H), 3.23 (dd, J = 5.7, 4.1 Hz, 4H) ppm. 427 355.45 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.22 (s, 1H), 9.05 (s, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.32 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 7.03 (d, J = 29.9 Hz, 1H), 6.54 (d, J = 67.9 Hz, 1H), 3.88 (s, 3H), 3.27 (s, 3H), 2.30 (d, J = 19.3 Hz, 2H) ppm. 428 383 0.6 1H NMR (400 MHz, Acetone-d6) δ 8.53 (s, 1H), 8.22 (s, 1H), 7.76 (dd, J = 7.9, 1.6 Hz, 1H), 7.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.53 (dtd, J = 17.0, 7.5, 1.5 Hz, 2H), 7.26 (s, 1H), 6.97 (s, 1H), 6.34 (s, 1H), 3.24-3.07 (m, 4H), 2.91 (s, 2H), 2.60-2.36 (m, 4H), 2.24 (s, 6H) ppm. 429 370 0.63 1H NMR (300 MHz, Acetone-d6) δ 8.93 (s, 1H), 7.65-7.52 (m, 2H), 7.48 (s, 1H), 7.40 (s, 1H), 7.01 (tt, J = 9.1, 2.3 Hz, 1H), 6.65 (s, 1H), 3.09 (dd, J = 19.9, 10.3 Hz, 2H), 2.82 (s, 2H), 2.73-2.55 (m, 3H), 2.32 (s, 3H), 2.01-1.93 (m, 1H), 1.79-1.53 (m, 3H) ppm. 430 353.09 0.6 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.44 (dd, J = 10.8, 5.1 Hz 2H), 7.35-7.24 (m, 1H), 7.09 (s, 1H), 6.88 (s, 1H), 6.46 (s, 1H), 4.77 (dtt, J = 48.8, 6.7, 3.4 Hz, 1H), 3.70 (dd, J = 14.2, 5.8 Hz, 2H), 3.56-3.41 (m, 2H), 2.31 (s, 3H), 2.01-1.91 (m, 1H), 1.90-1.74 (m, 3H) ppm. 431 419.49 0.65 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.69 (dd, J = 8.6, 1.1 Hz, 2H), 7.56-7.46 (m, 3H), 7.40-7.32 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.70 (s, 1H), 6.39 (s, 1H), 4.55 (d, J = 5.7 Hz, 2H), 4.40 (d, J = 5.5 Hz, 2H), 3.26 (s, 4H), 2.60 (d, J = 32.4 Hz, 6H), 2.34 (s, 3H), 1.49 (s, 3H) ppm. 432 435.19 0.6 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.46-7.34 (m, 1H), 7.30 (t, J = 2.2 Hz, 1H), 7.23 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.18 (t, J = 2.0 Hz, 1H), 6.89 (ddd, J = 8.3, 2.5, 0.7 Hz, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 4.71 (dq, J = 12.5, 6.4 Hz, 4H), 3.90 (d, J = 4.4 Hz, 3H), 3.58 (p, J = 6.4 Hz, 1H), 3.40-3.25 (m, 4H), 2.71-2.56 (m, 2H), 2.56-2.45 (m, 4H), 1.27 (t, J = 7.6 Hz, 3H) ppm. 433 442.44 0.65 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.16 (s, 1H), 7.60 (d, J = 6.4 Hz, 2H), 7.42-7.20 (m, 2H), 6.83 (s, 1H), 6.28 (s, 1H), 4.53 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4.32 (s, 1H), 3.41 (dd, J = 12.6, 6.3 Hz, 1H), 2.58 (s, 2H), 2.22 (s, 3H), 2.15-1.94 (m, 4H), 1.77-1.55 (m, 2H) ppm. 434 405.4 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.04 (s, 1H), 7.82 (dd, J = 8.6, 1.0 Hz, 2H), 7.55 (dd, J = 10.7, 5.2 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.14 (s, 1H), 6.88 (s, 1H), 6.28 (s, 1H), 3.91-3.73 (m, 2H), 3.66 (dd, J = 15.6, 8.0 Hz, 1H), 3.53 (dd, J = 8.5, 6.6 Hz, 1H), 3.11 (t, J = 4.9 Hz, 4H), 2.92 (p, J = 6.8 Hz, 1H), 2.66-2.53 (m, 2H), 2.49-2.44 (m, 2H), 2.22 (s, 3H), 2.09-1.91 (m, 1H), 1.78 (ddd, J = 15.6, 12.3, 8.2 Hz, 1H) ppm. 435 342.13 3.3 1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 60.2 Hz, 1H), 9.06 (s, 1H), 7.87 (dd, J = 8.9, 4.7 Hz, 3H), 7.42 (t, J = 8.7 Hz, 2H), 6.92-6.57 (m, 2H), 5.92 (d, J = 12.4 Hz, 1H), 3.24 (s, 4H), 1.97 (s, 4H) ppm. 436 405.49 0.64 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 8.24 (s, 1H), 7.63-7.56 (m, 2H), 7.47-7.39 (m, 2H), 7.28 (ddd, J = 7.4, 3.9, 1.1 Hz, 1H), 7.05 (s, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 6.32 (s, 1H), 4.63 (s, 2H), 4.21 (d, J = 5.9 Hz, 2H), 3.26 (s, 4H), 2.54 (s, 4H), 2.26 (s, 3H), 1.39 (s, 3H) ppm. 437 427.45 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 7.69 (ddd, J = 9.2, 6.0, 3.2 Hz, 1H), 7.67-7.48 (m, 1H), 7.40-7.23 (m, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 6.31 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 3.58-3.40 (m, 1H), 3.23-3.00 (m, 4H), 2.45-2.31 (m, 4H), 2.22 (s, 3H) ppm. 438 386.15 0.73 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.29 (s, 1H), 9.20 (s, 1H), 7.65 (d, J = 6.9 Hz, 2H), 7.28 (t, J = 23.5 Hz, 3H), 6.56 (s, 1H), 3.91 (s, 1H), 3.57 (s, 1H), 3.38 (q, J = 7.0 Hz, 1H), 3.34-3.11 (m, 2H), 2.94 (s, 1H), 2.74-2.53 (m, 2H), 2.29 (s, 3H), 1.87 (s, 2H) ppm. 439 437.17 0.61 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.61 (s, 1H), 7.46-7.36 (m, 2H), 7.24-7.14 (m, 2H), 6.77 (s, 1H), 6.61 (s, 1H), 6.41 (s, 1H), 4.78-4.62 (m, 4H), 3.66-3.53 (m, 1H), 3.37-3.25 (m, 4H), 2.57 (s, 3H), 2.55-2.51 (m, 4H), 2.34 (s, 3H) ppm. 440 376.11 3.02 1H NMR (400 MHz, DMSO-d6) δ 9.57 (d, J = 39.5 Hz, 1H), 9.10 (s, 1H), 7.94 (dd, J = 37.4, 25.7 Hz, 1H), 7.84-7.55 (m, 2H), 7.11-6.86 (m, 2H), 6.28 (t, J = 29.1 Hz, 1H), 3.85-3.68 (m, 4H), 3.23-3.00 (m, 4H) ppm. 441 392.13 3.58 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.26 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 6.90-6.72 (m, 2H), 5.91 (d, J = 11.4 Hz, 1H), 3.24 (s, 4H), 1.97 (s, 4H) ppm. 442 468.17 0.81 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.19 (s, 1H), 7.65 (d, J = 6.3 Hz, 2H), 7.42 (s, 1H), 7.28 (d, J = 14.4 Hz, 2H), 6.65 (s, 1H), 3.84 (s, 1H), 3.39 (d, J = 10.0 Hz, 2H), 3.34-3.22 (m, 1H), 2.95 (d, J = 20.8 Hz, 3H), 2.85-2.73 (m, 2H), 2.66-2.39 (m, 2H), 2.29 (s, 3H), 1.97 (s, 2H), 1.85-1.63 (m, 2H) ppm. 443 362 0.93 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.44-7.28 (m, 2H), 7.19 (d, J = 16.6 Hz, 1H), 6.75 (s, 1H), 6.67 (s, 1H), 4.04 (dd, J = 11.5, 7.3 Hz, 1H), 3.96-3.79 (m, 1H), 3.67 (d, J = 8.1 Hz, 1H), 3.61-3.27 (m, 3H), 2.46-2.26 (m, 4H) note: contains singlet for methyl\, 2.18-2.01 (m, 4H) ppm. note: contains singlet for methyl 444 398.21 0.85 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.16 (s, 1H), 7.67-7.55 (m, 2H), 7.25 (tt, J = 10.3, 8.1 Hz, 1H), 6.90 (s, 1H), 6.65 (s, 1H), 5.93 (s, 1H), 4.56 (dd, J = 15.6, 6.0 Hz, 4H), 3.50 (s, 2H), 3.25 (t, J = 6.9 Hz, 2H), 2.26 (t, J = 6.8 Hz, 2H), 2.21 (s, 3H) ppm. 445 427.18 0.59 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.6 Hz, 1H), 7.75 (ddt, J = 8.3, 6.6, 1.7 Hz, 1H), 7.25 (ddd, J = 8.3, 5.2, 2.5 Hz, 1H), 7.16 (ddd, J = 15.6, 8.0, 1.6 Hz, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.43 (s, 1H), 4.71 (dt, J = 13.0, 6.4 Hz, 4H), 3.66-3.49 (m, 1H), 3.36-3.24 (m, 4H), 2.59-2.46 (m, 4H), 2.35 (s, 3H) ppm. 446 425.38 0.64 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.70 (dd, J = 7.9, 1.7 Hz, 1H), 7.57 (dd, J = 7.9, 1.6 Hz, 1H), 7.41 (dtd, J = 20.3, 7.5, 1.7 Hz, 2H), 7.10 (s, 1H), 6.80 (s, 1H), 6.75 (s, 1H), 6.39 (s, 1H), 4.77-4.63 (m, 4H), 3.58 (p, J = 6.4 Hz, 1H), 3.36-3.19 (m, 4H), 2.60-2.44 (m, 4H), 2.33 (s, 3H) ppm. 447 326 0.74 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.24 (dt, J = 10.1, 2.3 Hz, 1H), 7.60 (s, 1H), 7.31 (s, 1H), 6.74 (s, 1H), 4.96 (dd, J = 8.3, 5.8 Hz, 2H), 4.74-4.53 (m, 2H), 4.29-4.07 (m, 1H), 2.30 (s, 3H) ppm. 448 342.19 0.8 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.15 (s, 2H), 7.72-7.59 (m, 2H), 7.16 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 12.4 Hz, 1H), 6.11 (d, J = 10.8 Hz, 1H), 5.99 (d, J = 0.8 Hz, 1H), 2.16 (s, 3H), 0.74-0.59 (m, 2H), 0.44-0.35 (m, 2H) ppm. 449 378 0.75 1H NMR (400 MHz, CDCl3) δ 9.12-8.95 (m, 2H), 8.93-8.81 (m, 1H), 7.79 (dd, J = 37.6, 5.3 Hz, 1H), 7.26 (q, J = 19.8 Hz, 2H), 6.89 (d, J = 18.4 Hz, 1H), 6.71 (d, J = 5.8 Hz, 1H), 4.79 (dd, J = 50.4, 12.6 Hz, 1H), 3.90 (s, 1H), 3.11 (dd, J = 26.1, 14.1 Hz, 1H), 2.68 (t, J = 11.3 Hz, 1H), 2.58 (dd, J = 22.1, 10.0 Hz, 2H), 2.38 (d, J = 8.5 Hz, 3H), 2.14 (d, J = 12.6 Hz, 4H-methine buried under the doublet), 1.87 (t, J = 14.9 Hz, 1H), 1.81-1.53 (m, 3H) ppm. 450 389 0.65 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.68 (s, 1H), 8.79 (d, J = 2.2 Hz, 1H), 7.89 (td, J = 8.9, 5.9 Hz, 1H), 7.64 (ddd, J = 11.6, 9.0, 2.7 Hz, 1H), 7.41-7.27 (m, 2H), 7.11 (d, J + 12.2 Hz, 1H), 6.90 (s, 1H), 6.40 (d, J = 12.2 Hz, 1H), 3.76 (d, J = 10.6 Hz, 2H), 3.48 (d, J = 9.1 Hz, 2H), 3.26-3.02 (m, 4H), 2.79 (d, J = 4.7 Hz, 3H) ppm. 451 355.13 0.53 1H NMR (400 MHz, DMSO-d6) δ 9.75 (d, J = 2.3 Hz, 1H), 9.44 (s, 1H), 9.18 (d, J = 8.5 Hz, 1H), 8.77 (dd, J = 5.4, 1.1 Hz, 1H), 8.73 (d, J = 5.1 Hz, 1H), 8.05 (dd, J = 8.6, 5.4 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 4.14 (m, 4H), 3.57 (m, 4H), 2.31 (d, J = 1.7 Hz, 3H) ppm. 452 324 0.73 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.66 (d, J = 23.4 Hz, 2H), 9.15 (s, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.4 Hz, 2H), 7.51 (d, J = 11.5 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.32 (s, 1H), 6.75 (d, J = 9.5 Hz, 1H), 3.60 (s, 1H), 3.42 (s, 2H), 3.20 (d, J = 24.0 Hz, 1H), 3.05 (s, 1H), 2.37 (s, 1H), 2.04-1.79 (m, 1H) ppm. 453 461.23 0.7 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.26 (dd, J = 7.8, 2.1 Hz, 2H), 7.11 (s, 1H), 6.88-6.74 (m, 2H), 6.68 (s, 1H), 6.43 (s, 1H), 3.37-3.20 (m, 4H), 2.84-2.65 (m, 3H), 2.62-2.44 (m, 6H), 2.35 (s, 3H) ppm. 454 433.3 0.63 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J = 15.6 Hz, 1H), 8.75 (d, J = 5.5 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.81 (s, 1H), 6.78 (s, 1H), 6.39 (s, 1H), 4.72 (dt, J = 14.5, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.37-3.22 (m, 4H), 2.75 (s, 3H), 2.56 (dd, J = 14.3, 9.3 Hz, 4H), 1.90 (tt, J = 8.4, 5.1 Hz, 1H), 1.03-0.90 (m, 2H), 0.84-0.70 (m, 2H) ppm. 455 429.39 0.72 1H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.06 (s, 1H), 7.83 (dd, J = 8.6, 1.0 Hz, 2H), 7.64-7.49 (m, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.26-7.07 (m, 4H), 7.01 (dt, J = 8.0, 5.7 Hz, 1H), 6.92 (s, 1H), 6.36 (s, 1H), 3.28 (d, J = 5.8 Hz, 4H), 3.18 (d, J = 5.3 Hz, 4H), 2.26 (d, J = 7.8 Hz, 3H) ppm. 456 428.35 0.73 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.19-7.14 (m, 2H), 7.05 (t, J = 2.1 Hz, 1H), 6.85 (d, J = 4.0 Hz, 1H), 6.77-6.65 (m, 2H), 6.40 (s, 1H), 4.11-3.98 (m, 2H), 3.91-3.78 (m, 5H), 3.73 (dd, J = 8.4, 7.0 Hz, 1H), 3.37-3.25 (m, 1H), 3.22-3.09 (m, 4H), 2.38-2.24 (m, 1H), 1.98 (ddd, J = 15.7, 12.4, 7.8 Hz, 1H) ppm. 457 389.1 0.62 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.13-7.05 (m, 2H), 6.79 (s, 2H), 6.69 (tt, J = 8.7, 2.3 Hz, 1H), 6.40 (s, 1H), 4.74 (dtt, J = 48.8, 6.8, 3.5 Hz, 1H), 3.65 (dd, J = 12.7, 7.2 Hz, 2H), 3.55-3.39 (m, 2H), 1.89 (d, J = 5.8 Hz, 3H), 1.86-1.69 (m, 4H) ppm. 458 439.22 0.31 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 7.98 (s, 1H), 7.73-7.50 (m, 2H), 7.21 (d, J = 111.2 Hz, 1H), 6.99 (tt, J = 9.0, 2.2 Hz, 1H), 4.18 (d, J = 67.2 Hz, 4H), 3.71 (d, J = 44.6 Hz, 4H), 2.42 (s, 3H), 2.06 (ddd, J = 12.7, 7.8, 4.7 Hz, 1H), 1.00-0.84 (m, 5H) ppm. 459 397 0.68 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.35-7.12 (m, 3H), 6.89-6.64 (m, 3H), 6.55 (s, 1H), 6.05 (s, 1H), 4.24 (s, 1H), 3.54 (s, 1H), 3.42 (s, 2H), 3.05 (dd, J = 9.5, 1.8 Hz, 1H), 2.71 (d, J = 9.4 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H), 2.01 (s, 1H), 1.93 (d, J = 9.5 Hz, 1H) ppm. 460 365.17 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.10 (s, 1H), 7.92-7.78 (m, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 1.4 Hz, 1H), 6.66 (s, 1H), 5.41 (d, J = 54.5 Hz, 1H), 3.74-3.45 (m, 3H), 3.43-3.33 (m, 1H), 2.24 (s, 2H), 1.81 (d, J = 8.1 Hz, 1H), 0.88 (dd, J = 4.9, 2.3 Hz, 2H), 0.79 (d, J = 8.1 Hz, 2H) ppm. 461 407.43 0.63 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.75-7.63 (m, 2H), 7.52 (dd, J = 10.6, 5.1 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 16.5 Hz, 1H), 6.81 (s, 1H), 6.68 (s, 1H), 6.39 (s, 1H), 3.71 (d, J = 12.6 Hz, 2H), 3.40 (s, 8H), 3.04 (d, J = 70.0 Hz, 6H), 2.36 (d, J = 9.2 Hz, 3H) ppm. 462 435.35 0.9 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.53-7.39 (m, 3H), 7.15-6.97 (m, 2H), 6.73 (s, 1H), 6.65 (s, 1H), 6.36 (s, 1H), 4.79-4.65 (m, 4H), 3.66-3.50 (m, 1H), 3.39-3.21 (m, 4H), 2.60-2.45 (m, 4H), 1.95-1.81 (m, 1H), 1.03-0.86 (m, 2H), 0.82-0.68 (m, 2H) ppm. 463 451.08 0.62 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.62 (s, 1H), 7.43-7.36 (m, 2H), 7.21 (dt, J = 7.4, 1.9 Hz, 2H), 6.82 (s, 1H), 6.63 (s, 1H), 6.45 (s, 1H), 4.78-4.65 (m, 4H), 3.66-3.50 (m, 1H), 3.38-3.28 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.57 (s, 3H), 2.56-2.51 (m, 4H), 1.32-1.21 (m, 3H) ppm. 464 380 0.63 1H NMR (400 MHz, Acetone-d6) δ 9.09 (s, 1H), 9.01 (d, J = 1.1 Hz, 1H), 8.92 (d, J = 5.5 Hz, 1H), 8.44 (s, 1H), 7.81 (dd, J = 5.5, 1.3 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 6.99 (s, 1H), 6.42 (s, 1H), 3.78 (d, J = 12.4 Hz, 2H), 3.30 (s, 3H), 3.25 (d, J = 6.2 Hz, 2H), 2.87-2.62 (m, 2H), 2.28 (s, 3H), 1.88-1.70 (m, 3H—methine contained in this muliplet), 1.38 (ddd, J = 15.6, 12.4, 4.1 Hz, 2H) ppm. 465 390.37 0.72 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.74-7.64 (m, 2H), 7.58-7.47 (m, 2H), 7.42-7.34 (m, 1H), 7.18 (t, J = 2.0 Hz, 1H), 7.14-7.08 (m, 1H), 6.82 (s, 1H), 6.59-6.52 (m, 1H), 6.24 (dd, J = 4.0, 2.0 Hz, 1H), 5.05 (td, J = 4.8, 2.2 Hz, 2H), 4.88 (td, J = 4.9, 1.8 Hz, 2H), 3.97-3.84 (m, 4H), 3.32-3.16 (m, 4H) ppm. 466 410 0.67 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.30 (s, 1H), 7.29-7.23 (m, 3H), 7.14 (s, 1H), 6.78 (tt, J = 8.7, 2.3 Hz, 1H), 6.70 (d, J = 1.7 Hz, 2H), 3.26-3.15 (m, 1H), 3.11 (d, J = 11.2 Hz, 1H), 2.74 (ddd, J = 11.6, 7.5, 3.5 Hz, 1H), 2.36 (s, 3H), 2.32-2.11 (m, 2H), 1.96 (d, J = 12.4 Hz, 1H), 1.88-1.57 (m, 3H), 1.51 (td, J = 12.2, 4.0 Hz, 1H), 0.53-0.37 (m, 4H) ppm. 467 496.22 0.63 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.23 (s, 1H), 6.78-6.65 (m, 3H), 6.61 (s, 1H), 6.39 (s, 1H), 6.23 (d, J = 11.5 Hz, 1H), 5.43 (d, J = 52.9 Hz, 1H), 3.96-3.63 (m, 4H), 3.63-3.44 (m, 4H), 3.39 (d, J = 10.2 Hz, 1H), 3.06-2.70 (m, 4H), 2.48 (d, J = 7.9 Hz, 4H), 2.34 (s, 3H), 2.17 (s, 1H), 0.89 (d, J = 7.8 Hz, 2H) ppm. 468 423.49 0.67 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.57-7.40 (m, 3H), 7.16 (t, J = 2.1 Hz, 1H), 7.10-6.98 (m, 1H), 6.84 (s, 1H), 6.70 (s, 1H), 6.45 (s, 1H), 4.85-4.57 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.43-3.18 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.60-2.40 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 469 441.24 0.66 1H NMR (300 MHz, CDCl3) δ 8.53 (d, J = 2.4 Hz, 1H), 7.75 (ddd, J = 9.2, 6.1, 3.1 Hz, 1H), 7.27-7.19 (m, 1H), 7.14 (s, 1H), 6.99 (ddd, J = 12.4, 7.0, 3.3 Hz, 1H), 6.80 (s, 1H), 6.73 (s, 1H), 6.43 (s, 1H), 4.67 (d, J = 5.6 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.46-3.15 (m, 4H), 2.67-2.47 (m, 4H), 2.36 (s, 3H), 1.44 (s, 3H) ppm. 470 407.47 0.65 1H NMR (300 MHz, CDCl3) δ 9.21 (d, J = 1.4 Hz, 1H), 9.21 (d, J = 1.4 Hz, 1H), 8.93 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.40 (dd, J = 2.5, 1.5 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.79 (s, 1H), 4.88-4.58 (m, 4H), 3.64 (p, J = 6.5 Hz, 1H), 3.04 (t, J = 4.6 Hz, 4H), 2.32 (s, 3H), 2.20 (s, 3H) ppm. 471 423.19 0.59 1H NMR (300 MHz, CDCl3) δ 9.16 (d, J = 1.3 Hz, 1H), 8.95 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.41 (dd, J = 2.5, 1.5 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.47 (s, 1H), 6.39 (d, J = 2.7 Hz, 1H), 4.81-4.63 (m, 4H), 3.78 (s, 3H), 3.59 (p, J = 6.5 Hz, 1H), 3.37-3.24 (m, 4H), 2.62-2.50 (m, 4H), 2.33 (s, 3H) ppm. 472 427.45 0.66 H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.14 (s, 1H), 7.77-7.53 (m, 2H), 7.23 (tt, J = 9.3, 2.2 Hz, 1H), 6.94 (s, 1H), 6.49 (s, 1H), 5.94 (s, 1H), 5.66 (d, J = 6.5 Hz, 1H), 4.56 (td, J = 6.4, 4.0 Hz, 2H), 4.45 (dt, J = 8.6, 5.9 Hz, 2H), 3.88 (d, J = 5.9 Hz, 1H), 3.74-3.51 (m, 1H), 2.89-2.69 (m, 1H), 2.62 (dd, J = 13.7, 8.2 Hz, 1H), 2.41 (dt, J = 8.9, 5.9 Hz, 2H), 2.31-2.19 (m, 1H), 2.15 (s, 3H), 1.67 (td, J = 12.6, 7.2 Hz, 1H) ppm. 473 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 2H), 7.52 (s, 1H), 7.29-7.19 (m, 1H), 7.18 (s, 1H), 6.62 (s, 1H), 4.58 (td, J = 6.5, 1.9 Hz, 2H), 4.50 (td, J = 6.0, 1.2 Hz, 2H), 3.69-3.60 (m, 1H), 3.29-3.21 (m, 1H), 2.97 (t, J = 8.4 Hz, 1H), 2.73 (dd, J = 14.9, 7.8 Hz, 1H), 2.59 (td, J = 8.7, 5.6 Hz, 1H), 2.44-2.38 (m, 1H), 2.26 (s, 3H), 1.79 (dt, J = 13.8, 8.3 Hz, 1H) ppm. 475 426.3 4.59 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.56 (m, 4H), 7.26 (t, J = 9.3 Hz, 1H), 6.81 (s, 1H), 3.84-3.75 (m, 4H), 3.28-3.15 (m, 4H) ppm. 476 423.17 0.6 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 7.4, 1.9 Hz, 1H), 7.19 (s, 1H), 7.16 (dd, J = 11.5, 8.4 Hz, 1H), 7.12-7.06 (m, 1H), 6.78 (s, 1H), 6.67 (s, 1H), 6.41 (s, 1H), 4.71 (dt, J = 14.3, 6.4 Hz, 4H), 3.65-3.52 (m, 1H), 3.38-3.26 (m, 4H), 2.59-2.49 (m, 4H), 2.41 (s, 3H), 2.35 (s, 3H) ppm. 477 406.18 0.8 1H NMR (300 MHz, CD3OD) δ 8.84 (s, 1H), 7.81 (ddd, J = 11.4, 6.9, 2.6 Hz, 1H), 7.64 (dddd, J = 9.0, 4.1, 2.6, 1.6 Hz, 1H), 7.45 (dt, J = 10.2, 8.7 Hz, 1H), 7.02 (q, J = 1.5 Hz, 2H), 4.43 (d, J = 11.0 Hz, 2H), 3.60 (d, J = 9.1 Hz, 2H), 3.20 (s, 4H), 2.96 (s, 3H) ppm. 478 475.11 0.63 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.76-7.67 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 6.83 (s, 1H), 6.67 (s, 1H), 6.42 (s, 1H), 4.79-4.63 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.24 (m, 4H), 2.59-2.46 (m, 4H), 2.35 (s, 3H) ppm. 479 361 0.61 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.66 (dd, J = 8.6, 1.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 6.83 (s, 1H exch), 6.58 (d, J = 5.0 Hz, 2H), 6.03 (s, 1H), 4.25 (s, 1H), 3.56 (s, 1H), 3.42 (s, 2H), 3.08 (d, J = 9.4 Hz, 1H), 2.72 (d, J = 9.5 Hz, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.04 (d, J = 9.6 Hz, 2H— heavy due to a broad peak underneath), 1.94 (d, J = 9.5 Hz, 1H) ppm. 480 508.23 0.58 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.40 (s, 1H), 6.84 (s, 1H), 6.77 (s, 1H), 6.65-6.51 (m, 2H), 6.41 (s, 1H), 6.18 (dt, J = 11.8, 2.1 Hz, 1H), 4.73 (dt, J = 14.6, 6.3 Hz, 4H), 3.79 (dd, J = 10.5, 6.1 Hz, 1H), 3.71-3.50 (m, 3H), 3.48-3.37 (m, 2H), 3.36-3.28 (m, 4H), 3.22 (dd, J = 9.5, 6.6 Hz, 1H), 2.82 (s, 1H), 2.70-2.57 (m, 2H), 2.58-2.49 (m, 4H), 2.32 (s, 3H), 2.18 (tt, J = 16.0, 6.7 Hz, 1H), 1.86 (ddd, J = 15.8, 12.7, 7.9 Hz, 1H), 1.75 (s, 1H) ppm. 481 378 0.6 1H NMR (400 MHz, Acetone-d6) δ 8.77 (s, 1H), 8.15 (s, 1H), 7.86 (dd, J = 8.6, 1.0 Hz, 2H), 7.54 (dd, J = 8.4, 7.6 Hz, 2H), 7.39-7.30 (m, 2H), 6.96 (s, 1H), 6.36 (s, 1H), 3.77 (d, J = 12.4 Hz, 2H), 3.29 (s, 3H), 3.25 (d, J = 6.2 Hz, 2H), 2.72 (td, J = 12.3, 2.4 Hz, 2H), 2.26 (s, 3H), 1.80 (d, J = 12.9 Hz, 2H), 1.76-1.67 (m, 1H), 1.37 (qd, J = 12.4, 4.0 Hz, 2H) ppm. 482 411.48 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.71-7.50 (m, 2H), 7.23 (tt, J = 9.3, 2.2 Hz, 1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.30 (s, 1H), 3.17-2.99 (m, 4H), 2.80-2.60 (m, 4H), 2.25 (d, J = 14.5 Hz, 3H), 1.77-1.56 (m, 1H), 0.58-0.40 (m, 2H), 0.41-0.23 (m, 2H) ppm. 483 418.5 0.65 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.74-7.67 (m, 2H), 7.56-7.47 (m, 2H), 7.41-7.33 (m, 1H), 7.24 (s, 2H), 6.68 (d, J = 5.5 Hz, 2H), 4.54 (d, J = 5.6 Hz, 2H), 4.37 (d, J = 5.7 Hz, 2H), 2.75 (d, J = 11.5 Hz, 2H), 2.60 (s, 2H), 2.54-2.41 (m, 1H), 2.37 (s, 3H), 2.21-2.08 (m, 2H), 1.89-1.75 (m, 4H), 1.46 (s, 3H) ppm. 484 445.31 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.87 (d, J = 2.3 Hz, 1H), 7.69-7.52 (m, 2H), 7.13 (s, 1H), 6.86 (s, 1H), 6.32 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 3.50-3.39 (m, 1H), 3.19-3.09 (m, 4H), 2.45-2.35 (m, 4H), 2.22 (s, 3H) ppm. 485 427.16 2.9 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.15 (s, 1H), 7.60 (d, J = 6.5 Hz, 2H), 7.24 (t, J = 9.3 Hz, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 5.82 (s, 1H), 3.89 (t, J = 6.9 Hz, 2H), 3.63-3.53 (m, 6H), 3.29-3.22 (m, 1H), 2.34 (m, 4H), 2.19 (s, 3H) ppm. 486 403.28 3.08 1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.89-7.79 (d, 2H), 7.56 (m, 4H), 7.38 (t, J = 7.4 Hz, 1H), 6.84 (s, 1H), 3.88 (d, J = 9.7 Hz, 2H), 3.51 (m, 2H), 3.19 (m, 4H), 2.85 (s, 3H) ppm. 487 1H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.17 (s, 1H), 7.74 (s, 1H), 7.69-7.58 (m, 2H), 7.25 (m, 2H), 6.85 (s, 1H), 5.18 (s, 1H), 4.57 (dd, J = 9.9, 4.3 Hz, 2H), 4.51 (dd, J = 13.1, 6.0 Hz, 2H), 3.82-3.71 (m, 1H), 2.92-2.70 (m, 4H), 2.29 (s, 3H), 2.21-1.97 (m, 2H) ppm. 488 354.83 0.73 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.74 (dd, J = 8.0, 0.9 Hz, 1H), 7.25 (dd, J = 7.7, 0.9 Hz, 1H), 6.76 (s, 2H), 6.64 (d, J = 1.6 Hz, 1H), 6.09 (s, 1H), 3.45-3.26 (m, 4H), 2.40-2.31 (s, 3H), 2.04 (td, J = 6.3, 3.1 Hz, 4H) ppm. 489 421.51 0.61 1H NMR (300 MHz, CDCl3) δ 9.19 (d, J = 1.4 Hz, 1H), 8.92 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.41 (dd, J = 2.5, 1.5 Hz, 1H), 7.18 (t, J = 2.0 Hz, 1H), 6.84 (s, 1H), 6.76 (s, 1H), 6.48 (s, 1H), 4.68 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.39-3.23 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 2.61-2.46 (m, 4H), 1.45 (s, 3H), 1.29 (t, J = 7.6 Hz, 3H) ppm. 490 400.24 0.8 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.15 (s, 1H), 7.72-7.60 (m, 2H), 7.28-7.17 (m, 1H), 7.04 (s, 1H), 6.46 (s, 1H), 6.04 (s, 1H), 5.31 (t, J = 6.2 Hz, 1H), 3.75 (t, J = 6.4 Hz, 2H), 3.06 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H), 1.95-1.83 (m, 3H), 1.65-1.56 (m, 1H), 1.20 (s, 3H) ppm. 491 522.23 0.65 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.22 (s, 1H), 6.76 (d, J = 10.3 Hz, 2H), 6.71-6.58 (m, 2H), 6.40 (s, 1H), 6.32 (dd, J = 12.0, 2.1 Hz, 1H), 4.77-4.60 (m, 4H), 3.92 (s, 1H), 3.59 (dd, J = 12.9, 6.4 Hz, 1H), 3.54-3.43 (m, 2H), 3.40 (s, 3H), 3.30 (dd, J = 11.0, 6.3 Hz, 5H), 3.24-3.15 (m, 1H), 2.59-2.46 (m, 4H), 2.34 (s, 3H), 2.07 (m, 2H) ppm. 492 401.18 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.10 (s, 1H), 8.04-7.91 (m, 1H), 7.75-7.58 (m, 2H), 6.73 (d, J = 1.6 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 5.41 (d, J = 53.7 Hz, 1H), 3.73-3.46 (m, 3H), 3.42-3.32 (m, 1H), 2.25 (d, J = 8.9 Hz, 2H), 1.82 (dd, J = 8.7, 4.0 Hz, 1H), 0.96-0.83 (m, 2H), 0.78 (dd, J = 8.2, 2.8 Hz, 2H) ppm. 493 372.42 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.15 (s, 1H), 7.59 (dd, J = 8.6, 2.1 Hz, 2H), 7.25 (dd, J = 10.4, 8.1 Hz, 1H), 6.68 (d, J = 8.9 Hz, 2H), 5.78 (s, 1H), 4.76 (t, J = 5.3 Hz, 1H), 3.80 (t, J = 7.4 Hz, 2H), 3.55 (dt, J = 18.8, 6.3 Hz, 4H), 2.75 (d, J = 7.7 Hz, 1H), 2.19 (s, 3H) ppm. 494 520.39 0.64 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.08 (t, J = 1.8 Hz, 1H), 6.73-6.67 (m, 3H), 6.57 (s, 1H), 6.37 (s, 1H), 6.08 (dt, J = 10.5, 1.9 Hz, 1H), 4.70 (p, J = 6.2 Hz, 4H), 4.45-4.31 (m, 1H), 4.22-4.15 (m, 2H), 3.81 (dd, J = 8.0, 4.3 Hz, 2H), 3.64-3.51 (m, 1H), 3.37 (s, 3H), 3.34-3.25 (m, 4H), 2.57-2.48 (m, 4H), 1.94-1.82 (m, 1H), 1.01-0.87 (m, 2H), 0.81-0.68 (m, 2H) ppm. 495 447 0.52 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.19 (s, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.72 (s, 1H), 6.68 (dd, J = 5.6, 1.7 Hz, 1H), 6.65 (s, 1H), 3.80-3.60 (m, 4H), 3.33 (s, 4H), 2.66 (s, 4H), 2.42 (s, 3H), 2.31 (s, 3H), 1.84 (s, 4H), 1.59 (dd, J = 6.2, 2.8 Hz, 4H) ppm. 496 400.24 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.14 (s, 1H), 7.65 (dd, J = 8.7, 2.1 Hz, 2H), 7.29-7.18 (m, 1H), 6.95 (s, 1H), 6.47 (s, 1H), 5.93 (s, 1H), 5.51 (s, 1H), 3.91-3.72 (m, 2H), 3.59 (dd, J = 14.5, 7.9 Hz, 1H), 3.08 (s, 2H), 2.14 (s, 3H), 1.97 (m, 1H), 1.86-1.71 (m, 4H), 1.49-1.39 (m, 1H) ppm. 497 360.09 3.36 498 401.18 0.64 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.12 (s, 1H), 8.05-7.90 (m, 1H), 7.68 (dt, J = 17.4, 5.7 Hz, 2H), 6.73 (d, J = 1.6 Hz, 1H), 6.62 (d, J = 1.5 Hz, 1H), 5.41 (d, J = 54.0 Hz, 1H), 3.72-3.44 (m, 3H), 3.37 (dd, J = 16.5, 9.3 Hz, 1H), 2.22 (d, J = 14.5 Hz, 2H), 1.83 (td, J = 8.0, 4.1 Hz, 1H), 0.87 (dd, J = 15.2, 5.6 Hz, 2H), 0.78 (dd, J = 8.1, 3.0 Hz, 2H) ppm. 499 374 0.59 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.16 (s, 1H), 8.31 (s, 1H), 8.24-8.09 (m, 1H), 7.78 (t, J = 7.2 Hz, 2H), 7.21 (s, 1H), 6.86 (s, 1H), 6.32 (s, 1H), 3.15 (d, J = 4.4 Hz, 3H), 2.56-2.40 (m, 4H—CH2s under solvent peak, 2.23 (s, 6H both CH3s co-incident) ppm. 500 427.21 0.81 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 9.16 (s, 1H), 7.60 (d, J = 6.9 Hz, 2H), 7.25 (dd, J = 10.3, 8.0 Hz, 1H), 6.94 (d, J = 10.3 Hz, 1H), 6.67-6.61 (m, 1H), 5.97 (s, 1H), 5.18 (m, 1H), 4.67 (m, 1H), 3.51-3.37 (m, 2H), 3.28-3.12 (m, 3H), 2.90 (s, 2H), 2.75 (s, 1H), 2.21 (s, 3H), 2.12 (s, 1H), 2.02 (s, 2H) ppm. 501 428.49 0.58 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.60 (ddd, J = 10.8, 6.8, 2.5 Hz, 1H), 7.47-7.38 (m, 1H), 7.37-7.28 (m, 2H), 7.20 (d, J = 4.0 Hz, 2H), 5.80 (s, 1H), 4.06 (t, J = 7.5 Hz, 2H), 3.87 (dd, J = 8.1, 5.4 Hz, 2H), 3.82-3.66 (m, 4H), 3.41-3.23 (m, 1H), 2.47 (d, J = 4.3 Hz, 4H), 2.33 (s, 3H) ppm. 502 392.49 0.56 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 5.79 (s, 1H), 4.06 (t, J = 7.5 Hz, 2H), 4.25-3.69 (m, 9H), 3.87 (dd, J = 8.0, 5.4 Hz, 2H), 3.83-3.66 (m, 4H), 3.39-3.24 (m, 1H), 3.47-3.24 (m, 1H), 2.47 (d, J = 4.2 Hz, 4H), 2.58-2.17 (m, 8H), 2.32 (s, 3H) ppm. 503 393.48 0.54 1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 8.44 (dd, J = 4.1, 1.0 Hz, 1H), 7.97-7.81 (m, 2H), 7.28-7.22 (m, 3H), 5.81 (s, 1H), 4.06 (t, J = 7.5 Hz, 2H), 3.87 (dd, J = 8.0, 5.4 Hz, 2H), 3.82-3.66 (m, 4H), 3.40-3.26 (m, 1H), 2.47 (d, J = 4.2 Hz, 4H), 2.34 (s, 3H) ppm. 504 411.52 0.54 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.57-7.47 (m, 1H), 7.31 (s, 1H), 7.28-7.25 (m, 1H), 7.21 (s, 1H), 5.83 (s, 1H), 4.07 (t, J = 7.5 Hz, 2H), 3.87 (dd, J = 8.1, 5.4 Hz, 2H), 3.83-3.69 (m, 4H), 3.39-3.25 (m, 1H), 2.47 (s, 4H), 2.35 (s, 3H) ppm. 505 543.56 0.68 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.27 (dd, J = 7.7, 2.4 Hz, 2H), 7.23-7.12 (m, 2H), 6.80 (tt, J = 8.7, 2.2 Hz, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 4.37-3.98 (m, 4H), 3.33 (d, J = 11.9 Hz, 2H), 3.18-3.06 (m, 1H), 3.04-2.81 (m, 4H), 2.78-2.60 (m, 1H), 2.34 (s, 3H), 2.08 (d, J = 10.3 Hz, 6H) ppm. 506 398.21 0.76 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.13 (s, 1H), 7.59 (dd, J = 8.7, 2.2 Hz, 2H), 7.23 (m, 1H), 6.70 (d, J = 4.5 Hz, 2H), 5.80 (s, 1H), 4.71 (dd, J = 7.8, 6.0 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.92 (t, J = 7.5 Hz, 2H), 3.52 (dd, J = 7.1, 5.4 Hz, 2H), 3.29-3.21 (m, 1H), 3.04 (m, 1H), 2.19 (s, 3H) ppm. 507 446.3 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.25 (s, 1H), 9.00 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.60 (dd, J = 2.5, 1.4 Hz, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 6.73 (s, 1H), 4.63 (dd, J = 7.8, 5.9 Hz, 1H), 4.39 (t, J = 6.2 Hz, 1H), 3.79 (d, J = 12.4 Hz, 2H), 2.77 (m, 3H), 1.91-1.63 (m, 4H), 1.45 (s, 1H), 1.16 (m, 2H) ppm. 508 384.21 0.81 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.67-7.52 (m, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.73 (s, 1H), 6.70 (s, 1H), 5.82 (s, 1H), 4.45 (t, J = 7.5 Hz, 2H), 4.06 (d, J = 9.4 Hz, 2H), 3.81 (d, J = 9.3 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.19 (s, 3H) ppm. 509 457.18 0.82 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.15 (s, 1H), 7.60 (dd, J = 8.5, 2.1 Hz, 2H), 7.24 (tt, J = 9.3, 2.2 Hz, 1H), 7.13 (s, 1H), 6.87 (s, 1H), 6.31 (s, 1H), 3.17 (d, J = 5.0 Hz, 4H), 2.86-2.71 (m, 4H), 2.23 (s, 3H), 1.26 (s, 6H) ppm. 510 411.22 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 9.14 (s, 1H), 7.59 (m, 2H), 7.28-7.17 (m, 1H), 6.73 (s, 1H), 6.68 (s, 1H), 5.80 (s, 1H), 3.89 (t, J = 7.0 Hz, 2H), 3.65-3.56 (m, 2H), 3.47-3.35 (m, 1H), 2.46 (m, 2H), 2.19 (s, 3H), 1.71 (m, 4H) ppm. 511 421.56 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.30 (d, J = 5.3 Hz, 1H), 9.08 (d, J = 1.0 Hz, 1H), 8.98 (d, J = 5.6 Hz, 1H), 7.68 (dd, J = 5.6, 1.3 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 6.41 (s, 1H), 4.58 (t, J = 6.5 Hz, 3H), 4.53-4.36 (m, 3H), 3.48 (dd, J = 12.4, 6.1 Hz, 1H), 3.20-3.12 (m, 4H), 2.81 (dt, J = 13.4, 6.6 Hz, 1H), 2.42 (dd, J = 13.0, 8.4 Hz, 4H), 1.19 (dd, J = 14.7, 7.0 Hz, 6H) ppm. 512 464.44 0.66 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.48 (s, 1H), 7.33 (s, 1H), 7.25 (d, J = 2.2 Hz, 2H), 6.89-6.77 (m, 1H), 6.64-6.33 (m, 2H), 4.79-4.64 (m, 4H), 3.73-3.61 (m, 4H), 3.62-3.48 (m, 1H), 2.58-2.38 (m, 4H) ppm. 513 404.24 0.84 1H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.26 (s, 1H), 9.04 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.59 (dd, J = 2.5, 1.4 Hz, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 6.53 (s, 1H), 4.75 (d, J = 6.3 Hz, 2H), 3.61 (d, J = 11.3 Hz, 2H), 3.49 (d, J = 11.3 Hz, 2H), 3.15 (m, 1H), 1.95 (d, J = 8.7 Hz, 1H) ppm. 514 447.34 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.26 (s, 1H), 9.02 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.60 (dd, J = 2.5, 1.4 Hz, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 6.77 (s, 1H), 4.59 (t, J = 6.5 Hz, 2H), 4.51 (t, J = 5.8 Hz, 2H), 3.51 (m, 1H), 3.30-3.15 (m, 4H), 2.49 (m, 4H) ppm. 515 444.17 0.82 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.77-7.49 (m, 3H), 7.44 (s, 1H), 7.35-7.15 (m, 1H), 6.70 (s, 1H), 4.80 (d, J = 6.1 Hz, 4H), 4.56 (s, 1H), 3.49 (d, J = 9.3 Hz, 2H), 3.30-3.06 (m, 2H), 2.67-2.47 (m, 5H), 2.45-2.17 (m, 6H) ppm. 516 442.19 0.78 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.18 (s, 1H), 7.75-7.57 (m, 3H), 7.24 (dd, J = 12.7, 5.6 Hz, 2H), 6.84 (s, 1H), 4.74 (s, 2H), 4.50 (d, J = 40.8 Hz, 3H), 3.44 (s, 1H), 2.30 (s, 3H), 2.24 (s, 2H), 1.92 (d, J = 12.4 Hz, 3H), 1.62 (d, J = 11.3 Hz, 2H) ppm. 517 372.14 0.78 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.18 (s, 1H), 8.21 (s, 1H), 7.70 (d, J = 6.5 Hz, 2H), 7.23 (dd, J = 10.4, 8.1 Hz, 1H), 7.04 (s, 1H), 6.78 (s, 1H), 4.48-4.40 (m, 2H), 4.09-4.03 (m, 2H), 2.29 (s, 3H) ppm. 518 400.28 0.81 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 9.14 (s, 1H), 7.65-7.53 (m, 2H), 7.30-7.13 (m, 1H), 6.76 (s, 1H), 6.66 (s, 1H), 5.81 (s, 1H), 5.33 (s, 1H), 3.78 (d, J = 7.6 Hz, 2H), 3.55 (d, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.84 (m, 1H), 0.91 (d, J = 6.8 Hz, 6H) ppm. 519 400.28 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.14 (s, 1H), 7.60 (dd, J = 8.7, 2.2 Hz, 2H), 7.30-7.15 (m, 1H), 6.75 (s, 1H), 6.64 (s, 1H), 5.79 (s, 1H), 4.36 (s, 1H), 3.75 (t, J = 7.5 Hz, 2H), 3.67 (t, J = 6.8 Hz, 2H), 2.80-2.64 (m, 1H), 2.19 (s, 3H), 1.06 (s, 6H) ppm. 520 386.23 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.17 (d, J = 2.8 Hz, 1H), 9.13 (d, J = 1.3 Hz, 1H), 7.71-7.56 (m, 2H), 7.22 (t, J = 9.3 Hz, 1H), 6.94 (s, 0.5H), 6.85 (s, 0.5H), 6.51 (s, 0.5H), 6.48 (s, 0.5H), 5.90 (s, 0.5H), 5.87 (s, 0.5H), 5.80-5.66 (m, 1H), 4.06-3.95 (m, 0.5H), 3.91-3.79 (m, 0.5H), 3.65 (m, 0.5H), 3.41 (m, 0.5H), 3.15 (d, J = 2.7 Hz, 3H), 2.79-2.67 (m, 1H), 2.28 (m, 1H), 2.18-2.06 (m, 4H), 1.70 (m, 1H) ppm. mixture of cis and trans 521 392.58 0.58 1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.18 (s, 1H), 9.02 (dd, J = 7.7, 1.3 Hz, 1H), 8.64 (dd, J = 8.2, 2.0 Hz, 1H), 8.57 (dd, J = 2.5, 1.4 Hz, 1H), 7.18 (s, 1H), 6.87 (s, 1H), 6.32 (s, 1H), 4.61 (dt, J = 12.3, 6.2 Hz, 2H), 4.37 (dd, J = 14.4, 8.2 Hz, 2H), 3.69 (d, J = 12.3 Hz, 2H), 2.81-2.63 (m, 3H), 2.23 (s, 3H), 1.78 (dd, J = 21.3, 11.5 Hz, 1H), 1.67 (d, J = 12.8 Hz, 2H), 1.16 (qd, J = 12.4, 3.7 Hz, 2H) ppm. 522 408.6 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.10 (s, 1H), 7.84-7.64 (m, 2H), 7.64-7.45 (m, 1H), 7.28-7.05 (m, 2H), 6.82 (s, 1H), 6.29 (s, 1H), 4.62 (dd, J = 7.9, 5.9 Hz, 2H), 4.46-4.25 (m, 2H), 3.68 (d, J = 12.3 Hz, 2H), 2.87-2.60 (m, 3H), 2.22 (s, 3H), 1.89-1.73 (m, 1H), 1.66 (d, J = 12.3 Hz, 2H), 1.15 (qd, J = 12.1, 3.6 Hz, 2H) ppm. 523 437.58 0.66 524 464.49 0.66 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.58 (ddd, J = 10.7, 6.8, 2.5 Hz, 1H), 7.48 (s, 1H), 7.45-7.39 (m, 1H), 7.34 (dd, J = 9.0, 7.8 Hz, 2H), 6.54 (dd, J = 87.5, 31.4 Hz, 2H), 4.80-4.63 (m, 4H), 3.72-3.49 (m, 5H), 2.53-2.36 (m, 4H) ppm. 525 446.44 0.64 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.56-7.43 (m, 4H), 7.40 (s, 1H), 7.08 (tdd, J = 7.4, 4.9, 2.6 Hz, 1H), 6.54 (dd, J = 88.5, 32.4 Hz, 2H), 4.79-4.60 (m, 4H), 3.71-3.49 (m, 5H), 2.52-2.37 (m, 4H) ppm. 526 428.58 0.64 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.74-7.65 (m, 2H), 7.53 (dd, J = 11.3, 5.8 Hz, 3H), 7.39 (ddd, J = 9.1, 8.7, 4.9 Hz, 2H), 6.53 (dd, J = 89.5, 33.3 Hz, 2H), 4.80-4.62 (m, 4H), 3.70-3.50 (m, 5H),2.51-2.39 (m, 4H) ppm. 527 384.25 0.9 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.15 (s, 1H), 7.60 (m, 2H), 7.23 (m, 1H), 7.03 (m, 1H), 6.78 (s, 1H), 6.13 (s, 1H), 4.71 (d, J = 6.4 Hz, 2H), 3.54 (d, J = 11.2 Hz, 2H), 3.41 (d, J = 11.0 Hz, 2H), 3.12 (m, 1H), 2.25 (s, 3H), 1.93 (d, J = 8.6 Hz, 1H) ppm. 528 412.35 0.68 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.16 (s, 1H), 7.68-7.52 (m, 2H), 7.31 (s, 1H), 7.29-7.18 (m, 1H), 6.75 (s, 1H), 6.35 (s, 1H), 3.97 (d, J = 11.4 Hz, 1H), 3.83 (m, 3H), 3.10 (td, J = 11.1, 3.9 Hz, 1H), 2.79-2.68 (m, 1H), 2.68-2.57 (m, 1H), 2.22 (s, 3H), 2.09-1.94 (m, 2H), 1.61 (m, 3H) ppm. 529 372.51 0.6 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.62 (s, 1H), 7.39 (dd, J = 8.0, 2.2 Hz, 2H), 7.23 (s, 1H), 6.85 (tt, J = 8.8, 2.3 Hz, 1H), 6.19 (s, 1H), 3.77-3.61 (m, 4H), 3.20-3.08 (m, 4H), 2.37 (s, 3H) ppm. 530 441.54 0.66 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.39 (s, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 2H), 6.82 (s, 1H), 6.65 (s, 1H), 6.52 (ddd, J = 8.8, 5.5, 2.2 Hz, 1H), 6.10 (s, 1H), 3.77 (td, J = 8.4, 4.4 Hz, 2H), 3.61 (dd, J = 10.1, 6.4 Hz, 1H), 3.47 (dt, J = 28.4, 14.3 Hz, 2H), 3.17 (s, 4H), 2.87 (d, J = 13.9 Hz, 4H), 2.02 (s, 4H), 1.89 (dd, J = 27.7, 16.6 Hz, 1H) ppm. 531 441.49 0.66 1H NMR (300 MHz, CD3OD + CDCl3) δ 8.70 (s, 1H), 7.41 (dd, J = 7.8, 1.9 Hz, 2H), 7.21 (s, 1H), 6.97-6.74 (m, 2H), 6.42 (s, 1H), 3.99 (ddd, J = 15.4, 8.6, 5.7 Hz, 2H), 3.90-3.60 (m, 2H), 3.28 (t, J = 5.0 Hz, 4H), 3.16-3.00 (m, 1H), 2.86-2.56 (m, 4H), 2.33 (s, 3H), 2.25-2.08 (m, 1H), 1.99-1.88 (m, 1H) ppm. 532 429.48 0.62 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.45 (d, J = 4.3 Hz, 1H), 7.90 (ddd, J = 17.5, 12.1, 4.8 Hz, 3H), 7.57 (s, 1H), 7.40 (s, 1H), 6.61 (t, J = 56.2 Hz, 1H), 6.38 (s, 1H), 4.79-4.63 (m, 4H), 3.70-3.61 (m, 4H), 3.55 (dd, J = 12.8, 6.5 Hz, 1H), 2.51-2.38 (m, 4H) ppm. 533 472.5 0.73 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 6.14 (s, 1H), 3.53 (t, J = 5.1 Hz, 8H), 2.36 (s, 3H), 1.51 (s, 9H) ppm. 534 501.53 0.66 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.25 (dd, J = 7.9, 2.2 Hz, 2H), 7.10 (d, J = 1.9 Hz, 1H), 6.87-6.69 (m, 3H), 6.41 (s, 1H), 4.01 (s, 2H), 3.36-3.18 (m, 4H), 2.82 (dd, J = 5.7, 2.9 Hz, 4H), 2.61 (d, J = 13.9 Hz, 1H), 2.42 (d, J = 13.9 Hz, 1H), 2.35 (s, 3H), 2.13 (s, 3H), 1.23 (s, 3H) ppm. 535 393.52 0.56 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.28 (s, 2H), 9.20 (s, 1H), 9.16 (s, 1H), 7.14 (s, 1H), 6.89 (s, 1H), 6.32 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.54-3.39 (m, 1H), 3.23-3.12 (m, 3H), 2.47-2.32 (m, 4H), 2.23 (s, 3H) ppm. 536 421.21 0.62 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.21 (s, 1H), 9.02 (d, J = 1.2 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 2.5, 1.4 Hz, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 6.40 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.50-3.41 (m, 1H), 3.16 (d, J = 4.7 Hz, 4H), 2.92-2.70 (m, 1H), 2.35 (d, J = 44.0 Hz, 4H), 1.21 (d, J = 6.9 Hz, 6H) ppm. 537 428.18 2.22 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 7.48 (s, 1H), 7.34-7.21 (m, 4H), 6.84 (tt, J = 8.7, 2.2 Hz, 1H), 4.57 (d, J = 6.2 Hz, 4H), 3.97 (t, J = 4.4 Hz, 4H), 3.91-3.79 (m, 1H), 3.02 (s, 4H), 2.40 (s, 3H) ppm. 538 410.21 2.13 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 7.48 (s, 1H), 7.34-7.21 (m, 4H), 6.84 (tt, J = 8.7, 2.2 Hz, 1H), 4.57 (d, J = 6.2 Hz, 4H), 3.97 (t, J = 4.4 Hz, 4H), 3.91-3.79 (m, 1H), 3.02 (s, 4H), 2.40 (s, 3H) ppm. 539 419 0.61 1H NMR (400 MHz, Acetone-d6) δ 9.11 (d, J = 1.3 Hz, 1H), 8.94 (s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.48 (dd, J = 2.5, 1.5 Hz, 1H), 8.30 (s, 1H), 7.93 (s, 2H), 6.90-6.63 (m, 2H), 4.00 (t, J = 7.0 Hz, 2H), 3.74-3.57 (m, 5H), 3.40-3.23 (m, 2H), 1.94-1.75 (m, 1H), 0.91 (ddd, J = 8.4, 6.4, 4.2 Hz, 2H), 0.69 (dt, J = 6.5, 4.3 Hz, 2H) ppm. 540 482.54 0.68 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 6.83 (tt, J = 8.7, 2.2 Hz, 1H), 6.45 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.75-3.62 (m, 4H), 3.61-3.51 (m, 1H), 2.54-2.34 (m, 4H) ppm. 541 412.21 0.64 1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 2H), 7.35 (s, 1H), 7.23 (tt, J = 9.3, 4.6 Hz, 1H), 6.80 (s, 1H), 6.37 (s, 1H), 4.32 (s, 4H), 3.05-2.96 (m, 2H), 2.23 (s, 3H), 1.83-1.71 (m, 2H), 1.58 (m, 2H) ppm. 542 425.18 0.74 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.14 (s, 1H), 7.65-7.54 (m, 2H), 7.28-7.18 (m, 1H), 6.74 (s, 2H), 5.84 (s, 1H), 4.99-4.88 (m, 1H), 4.00 (t, J = 7.7 Hz, 2H), 3.88-3.80 (m, 2H), 3.53 (t, J = 6.9 Hz, 2H), 2.27 (t, J = 8.0 Hz, 2H), 2.20 (s, 3H), 2.02-1.90 (m, 2H) ppm. 543 412.56 0.9 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.16 (s, 1H), 7.61 (dd, J = 8.6, 2.1 Hz, 2H), 7.35 (s, 1H), 7.27-7.18 (m, 1H), 6.77 (s, 1H), 6.34 (s, 1H), 3.70-3.60 (m, 2H), 3.07 (s, 2H), 3.04-2.96 (m, 2H), 2.23 (s, 3H), 1.99 (m, 4H), 1.86-1.65 (m, 2H) ppm. 544 407 0.48 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 9.12 (s, 2H), 8.39 (s, 1H), 6.68 (s, 1H), 6.67-6.57 (m, 2H), 5.98 (s, 1H), 4.00 (t, J = 7.0 Hz, 2H), 3.75 (dd, J = 10.5, 5.0 Hz, 6H), 3.40-3.26 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 2.46 (s, 4H), 1.24 (t, J = 7.6 Hz, 3H) ppm. 545 464.53 0.66 1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.64 (s, 1H), 7.57-7.43 (m, 3H), 7.39 (s, 1H), 7.15-7.03 (m, 1H), 6.44 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.74-3.62 (m, 4H), 3.61-3.49 (m, 1H), 2.54-2.38 (m, 4H) ppm. 546 482.45 0.68 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.64-7.52 (m, 2H), 7.49-7.30 (m, 3H), 6.44 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.75-3.60 (m, 4H), 3.60-3.50 (m, 1H), 2.55-2.36 (m, 4H) ppm. 547 446.53 0.66 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.73-7.66 (m, 3H), 7.54 (dd, J = 10.6, 5.1 Hz, 2H), 7.44-7.35 (m, 2H), 6.43 (s, 1H), 4.77-4.63 (m, 4H), 3.76-3.61 (m, 4H), 3.60-3.51 (m, 1H), 2.53-2.39 (m, 4H) ppm. 548 447.52 0.65 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.45 (dd, J = 4.8, 0.9 Hz, 1H), 7.98-7.88 (m, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.42 (s, 1H), 7.27 (d, J = 1.2 Hz, 1H), 6.44 (s, 1H), 4.79-4.64 (m, 4H), 3.74-3.62 (m, 4H), 3.52 (s, 1H), 2.54-2.39 (m, 4H) ppm. 549 407.56 0.58 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.27 (s, 2H), 9.20 (s, 1H), 9.15 (s, 1H), 7.14 (s, 1H), 6.96 (s, 1H), 6.35 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.55-3.39 (m, 1H), 3.24-3.03 (m, 4H), 2.59-2.51 (m, 2H), 2.38 (dd, J = 26.7, 22.1 Hz, 4H), 1.19 (q, J = 7.8 Hz, 3H) ppm. 550 435.55 0.61 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.26 (s, 2H), 9.21 (s, 1H), 9.15 (s, 1H), 7.25 (s, 1H), 7.09 (s, 1H), 6.51 (s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.54-3.38 (m, 1H), 3.22-3.04 (m, 4H), 2.47-2.33 (m, 4H), 1.28 (s, 9H) ppm. 551 372.27 0.72 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.67-7.52 (m, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.73 (s, 1H), 6.69 (s, 1H), 5.81 (s, 1H), 5.48 (s, 1H), 3.72 (d, J = 7.2 Hz, 2H), 3.59 (d, J = 7.1 Hz, 2H), 2.19 (s, 3H), 1.46 (s, 3H) ppm. 552 439.56 0.68 1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.16 (s, 1H), 7.64-7.52 (m, 2H), 7.33 (s, 1H), 7.29-7.16 (m, 1H), 6.79 (s, 1H), 6.35 (s, 1H), 3.63 (d, J = 11.2 Hz, 1H), 3.57-3.42 (m, 2H), 3.02 (m, 1H), 2.94-2.66 (m, 4H), 2.23 (s, 3H) ppm. 553 386.59 0.76 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.67-7.54 (m, 2H), 7.23 (tt, J = 9.3, 2.2 Hz, 1H), 6.75 (s, 1H), 6.68 (s, 1H), 5.82 (s, 1H), 5.40 (s, 1H), 3.74 (d, J = 7.4 Hz, 2H), 3.56 (d, J = 7.4 Hz, 2H), 2.20 (s, 3H), 1.72 (q, J = 7.2 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm. 554 497.52 0.89 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.62 (s, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 7.27-7.23 (m, 1H), 6.83 (tt, J = 8.7, 2.2 Hz, 1H), 6.43 (s, 1H), 4.44 (s, 1H), 3.73-3.61 (m, 4H), 3.59-3.50 (m, 4H), 3.41-3.27 (m, 2H), 2.98 (d, J = 7.3 Hz, 1H), 1.23-1.11 (m, 3H) ppm. 555 468.49 0.88 1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 6.84 (ddd, J = 8.7, 5.5, 2.3 Hz, 1H), 6.45 (s, 1H), 3.82-3.74 (m, 2H), 3.74-3.66 (m, 2H), 3.61 (dd, J = 10.6, 5.3 Hz, 4H), 2.21 (d, J = 19.0 Hz, 3H) ppm. 556 426.55 0.67 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.83 (tt, J = 8.7, 2.2 Hz, 1H), 6.45 (s, 1H), 3.64-3.54 (m, 4H), 3.08-2.92 (m, 4H) ppm. 557 526.23 1.09 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 6.83 (tt, J = 8.7, 2.3 Hz, 1H), 6.45 (s, 1H), 3.70-3.45 (m, 8H), 1.52 (s, 9H) ppm. 558 371 0.64 freebase—1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 7.69 (ddd, J = 9.2, 6.0, 3.2 Hz, 1H), 7.59 (ddd, J = 11.1, 9.2, 4.8 Hz, 1H), 7.37-7.25 (m, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 6.28 (s, 1H), 3.31 (s, 2H), 3.13-2.95 (m, 4H), 2.93-2.76 (m, 4H), 2.21 (s, 3H) ppm. bis HCl salt—1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.51 (s, 1H), 8.84 (d, J = 2.4 Hz, 1H), 7.79 (ddd, J = 9.1, 6.0, 3.2 Hz, 1H), 7.60 (ddd, J = 11.0, 9.3, 4.8 Hz, 1H), 7.43-7.19 (m, 1H), 7.04 (s, 1H), 6.49 (s, 1H), 3.59-3.38 (m, 4H), 3.29 (s, 4H), 2.26 (s, 3H) ppm. 559 455.32 3.05 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.57 (ddd, J = 10.9, 6.8, 2.5 Hz, 1H), 7.45-7.35 (m, 1H), 7.32 (dd, J = 9.3, 8.1 Hz, 1H), 7.13 (t, J = 2.0 Hz, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.44 (s, 1H), 4.83-4.61 (m, 4H), 3.69-3.50 (m, 1H), 3.43-3.21 (m, 4H), 2.63-2.40 (m, 6H), 1.67 (dt, J = 14.7, 7.4 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H) ppm. 560 373.5 0.63 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.26 (dd, J = 7.8, 2.2 Hz, 2H), 6.92-6.76 (m, 3H), 6.60 (d, J = 1.3 Hz, 1H), 3.95-3.76 (m, 4H), 3.63-3.46 (m, 4H), 2.43 (s, 3H) ppm. 561 425 0.76 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.25-7.19 (m, 3H), 6.79 (tt, J = 8.7, 2.3 Hz, 1H), 6.73 (s, 1H), 6.68 (s, 1H), 6.41 (s, 1H), 4.19-4.08 (m, 1H), 3.87-3.75 (m, 2H), 3.73-3.65 (m, 1H), 3.06 (td, J = 12.7, 3.8 Hz, 1H), 2.76 (td, J = 12.2, 3.5 Hz, 1H), 2.53 (dd, J = 12.4, 11.3 Hz, 1H), 2.46 (dd, J = 9.6, 6.3 Hz, 2H), 2.33 (s, 3H), 2.27 (td, J = 13.1, 7.6 Hz, 1H), 1.80-1.65 (m, 1H) ppm. 562 442.62 0.62 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.21 (s, 2H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 6.13 (s, 1H), 4.05-3.91 (m, 2H), 3.83 (dd, J = 15.9, 8.2 Hz, 1H), 3.72 (dd, J = 8.5, 7.0 Hz, 1H), 3.56 (t, J = 5.1 Hz, 4H), 3.03 (p, J = 7.1 Hz, 1H), 2.66 (dt, J = 10.4, 5.0 Hz, 2H), 2.60-2.47 (m, 2H), 2.36 (s, 3H), 2.11 (ddt, J = 7.6, 4.3, 3.7 Hz, 1H), 1.93 (ddd, J = 15.9, 12.2, 8.2 Hz, 1H) ppm. 563 399.52 0.89 1H NMR (300 MHz, DMSO) δ 9.33 (s, 1H), 9.17 (s, 1H), 7.64 (m, 2H), 7.26 (m, 1H), 7.08 (s, 1H), 5.77 (s, 1H), 4.71 (dd, J = 7.8, 6.1 Hz, 2H), 4.31 (t, J = 6.0 Hz, 2H), 4.02 (t, J = 8.0 Hz, 2H), 3.63 (dd, J = 8.0, 5.3 Hz, 2H), 3.26 (m, 1H), 3.01 (m, 1H), 2.22 (s, 3H) ppm. 564 496.53 0.68 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.83 (tt, J = 8.7, 2.2 Hz, 1H), 6.44 (s, 1H), 4.07-3.90 (m, 2H), 3.83 (dd, J = 15.9, 8.1 Hz, 1H), 3.72 (dd, J = 8.5, 6.8 Hz, 1H), 3.62 (t, J = 5.1 Hz, 4H), 3.11-2.98 (m, 1H), 2.74-2.61 (m, 2H), 2.60-2.43 (m, 2H), 2.17-2.05 (m, 1H), 1.93 (ddd, J = 15.6, 12.3, 8.2 Hz, 1H) ppm. 565 443.25 0.65 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.30-7.26 (m, 2H), 7.19 (s, 1H), 7.17 (s, 1H), 6.80 (tt, J = 8.7, 2.3 Hz, 1H), 6.16 (s, 1H), 4.24 (ddd, J = 12.3, 7.9, 4.4 Hz, 2H), 4.21-4.15 (m, 2H), 3.00-2.88 (m, 2H), 2.53 (tt, J = 11.1, 3.9 Hz, 1H), 2.35 (s, 3H), 2.00 (dd, J = 13.6, 3.3 Hz, 2H), 1.85-1.70 (m, 2H), 1.31-1.26 (m, 3H) ppm. 566 427 0.65 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.23 (dd, J = 7.9, 2.2 Hz, 2H), 7.17 (s, 1H), 6.77 (tt, J = 8.7, 2.3 Hz, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 6.40 (s, 1H), 3.90 (dd, J = 11.3, 3.2 Hz, 1H), 3.77 (dtd, J = 13.8, 11.3, 2.5 Hz, 2H), 3.66 (d, J = 10.8 Hz, 1H), 3.46 (d, J = 10.3 Hz, 1H), 3.41-3.33 (m, 1H), 2.99 (td, J = 11.8, 3.0 Hz, 1H), 2.93-2.86 (m, 1H), 2.74 (d, J = 11.4 Hz, 1H), 2.60-2.39 (m, 4H), 2.33 (s, 3H) ppm. 567 482.49 0.66 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.95 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 7.8, 2.2 Hz, 2H), 6.84 (tt, J = 8.7, 2.2 Hz, 1H), 6.75 (d, J = 2.1 Hz, 1H), 4.72 (dt, J = 12.4, 6.4 Hz, 4H), 3.64-3.46 (m, 5H), 2.63-2.47 (m, 4H) ppm. 568 389.15 0.62 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.30-7.27 (m, 3H), 7.24 (s, 1H), 7.18 (s, 1H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 6.16 (s, 1H), 4.72 (dtt, J = 47.8, 7.3, 3.7 Hz, 1H), 4.03-3.88 (m, 1H), 3.67-3.51 (m, 2H), 3.45-3.35 (m, 1H), 2.35 (s, 3H), 2.12-1.97 (m, 1H), 1.97-1.79 (m, 2H), 1.70-1.59 (m, 1H) ppm. 569 401.17 0.59 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.31-7.25 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 6.17 (s, 1H), 3.88 (dt, J = 13.3, 4.3 Hz, 2H), 3.40 (ddd, J = 13.4, 10.0, 3.8 Hz, 2H), 2.35 (s, 3H), 1.78-1.62 (m, 4H), 1.31 (d, J = 4.9 Hz, 3H) ppm. 570 399.19 0.6 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.30-7.26 (m, 2H), 7.23 (s, 1H), 7.20 (s, 1H), 6.81 (ddt, J = 7.9, 5.6, 2.8 Hz, 1H), 5.82 (s, 1H), 3.98 (s, 3H), 3.94 (s, 2H), 3.90 (dt, J = 7.0, 4.4 Hz, 3H), 2.34 (s, 3H), 2.22 (t, J = 7.0 Hz, 2H) ppm. 571 385.19 0.6 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.22 (s, 2H), 7.20 (s, 1H), 6.81 (ddd, J = 8.7, 5.5, 2.3 Hz, 1H), 5.81 (s, 1H), 4.60 (t, J = 7.5 Hz, 2H), 4.18 (dd, J = 10.6, 5.5 Hz, 4H), 2.93 (t, J = 7.5 Hz, 2H), 2.34 (s, 3H) ppm. 572 401.17 0.6 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.29-7.25 (m, 3H), 7.18 (d, J = 5.8 Hz, 1H), 6.80 (ddt, J = 7.8, 3.3, 2.3 Hz, 1H), 5.81 (s, 1H), 4.05-3.84 (m, 4H), 2.77 (tt, J = 8.4, 6.0 Hz, 1H), 2.33 (s, 3H), 1.27 (s, 6H) ppm. 573 553.38 0.54 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.14 (s, 1H), 7.58 (d, J = 6.4 Hz, 2H), 7.23 (t, J = 9.2 Hz, 1H), 6.78 (d, J = 1.6 Hz, 2H), 6.02 (s, 1H), 3.08 (d, 8H), 2.67-2.59 (m, 8H), 1.04 (s, 18H) ppm. 574 553.33 0.5 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.14 (s, 1H), 7.58 (d, J = 6.5 Hz, 2H), 7.23 (t, J = 9.3 Hz, 1H), 6.80 (d, J = 1.6 Hz, 2H), 6.07 (s, 1H), 4.57 (t, J = 6.5 Hz, 4H), 4.47 (t, J = 6.0 Hz, 4H), 3.49-3.40 (m, 2H), 3.19-3.09 (m, 8H), 2.45-2.36 (m, 8H) ppm.

TABLE 3A Analytical Data LC/MS Cmpd Ret. No. in LCMS Time PRV2 (M + H) (min) ¹H-NMR 575 448.22 0.63 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.89 (dt, J = 7.7, 1.9 Hz, 1H), 7.74-7.58 (m, 2H), 7.21 (t, J = 2.2 Hz, 1H), 6.83 (t, J = 1.8 Hz, 1H), 6.73 (s, 1H), 6.41 (t, J = 1.7 Hz, 1H), 4.19 (d, J = 12.2 Hz, 2H), 3.77 (d, J = 5.5 Hz, 4H), 2.87 (s, 2H), 2.65 (s, 4H), 2.36 (s, 3H) ppm. 576 430.65 0.62 1H NMR (300 MHz, MeOD + CDCl3) δ 9.16 (d, J = 13.5 Hz, 1H), 8.99 (d, J = 12.8 Hz, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 7.49 (s, 1H), 6.57 (dd, J = 87.9, 31.7 Hz, 2H), 4.96-4.55 (m, 4H), 3.93-3.46 (m, 5H), 2.48 (s, 4H) ppm. 577 455.71 0.71 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.58 (ddd, J = 10.9, 6.8, 2.5 Hz, 1H), 7.39 (tdd, J = 4.0, 3.2, 1.4 Hz, 1H), 7.32 (dd, J = 9.3, 8.1 Hz, 1H), 7.09 (t, J = 2.0 Hz, 1H), 6.84 (s, 1H), 6.70 (s, 1H), 6.46 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.40-3.16 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.57 (dd, J = 10.9, 5.9 Hz, 4H), 1.44 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 578 460.29 0.6 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 6.6 Hz, 1H), 7.98 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.72-7.58 (m, 2H), 7.23 (d, J = 4.5 Hz, 2H), 6.14 (s, 1H), 4.81-4.62 (m, 4H), 3.62-3.57 (m, 4H), 3.55 (dd, J = 12.9, 6.5 Hz, 1H), 2.47 (dd, J = 15.4, 10.4 Hz, 4H), 2.35 (s, 3H) ppm. 579 478.2 0.69 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.57 (ddd, J = 10.7, 6.8, 2.5 Hz, 1H), 7.50 (s, 1H), 7.42 (ddd, J = 6.3, 4.6, 3.2 Hz, 1H), 7.38-7.30 (m, 2H), 6.37 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.73-3.60 (m, 4H), 3.54 (dd, J = 12.8, 6.4 Hz, 1H), 2.55-2.33 (m, 4H), 1.95 (t, J = 18.3 Hz, 3H) ppm. 580 442.66 0.63 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 4.7 Hz, 2H), 6.81 (tt, J = 8.7, 2.2 Hz, 1H), 6.13 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.29 (d, J = 5.7 Hz, 2H), 3.78-3.41 (m, 4H), 2.63-2.42 (m, 4H), 2.35 (s, 3H), 1.40 (s, 3H) ppm. 581 428.24 0.75 1H NMR (300 MHz, MeOD) δ 8.84 (s, 1H), 8.12 (s, 1H), 7.58-7.42 (m, 3H), 7.24 (s, 1H), 6.92 (tt, J = 9.0, 2.2 Hz, 1H), 6.75 (s, 1H), 4.76-4.61 (m, 4H), 4.54 (dd, J = 10.3, 1.8 Hz, 1H), 4.06 (dd, J = 11.6, 2.1 Hz, 1H), 3.85 (td, J = 11.6, 2.2 Hz, 1H), 3.64-3.52 (m, 1H), 2.84 (dd, J = 34.1, 11.5 Hz, 2H), 2.32 (s, 3H), 2.21 (td, J = 11.5, 3.4 Hz, 1H), 2.06 (t, J = 10.9 Hz, 1H) ppm. 582 483.84 2.82 1H NMR (300 MHz, DMSO-D6) δ 9.63 (s, 1H), 9.20 (s, 1H), 7.71 (d, J = 7.3 Hz, 2H), 7.59 (s, 1H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.06 (s, 1H), 6.69 (s, 1H), 3.59 (t, J = 4.6 Hz, 4H), 3.53-3.39 (m, 4H), 3.39-3.26 (m, 4H), 3.21 (t, J = 4.7 Hz, 4H), 2.28 (s, 3H) ppm. 583 407.61 0.57 1H NMR (300 MHz, CDCl3) δ 9.25 (d, J = 1.3 Hz, 1H), 8.93 (s, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.40 (dd, J = 2.5, 1.5 Hz, 1H), 7.36 (d, J = 23.3 Hz, 2H), 6.83 (d, J = 13.5 Hz, 2H), 4.75-4.56 (m, 4H), 3.63-3.44 (m, 3H), 2.59 (s, 4H), 2.41 (d, J = 8.5 Hz, 7H) ppm. 584 457.38 0.74 1H NMR (300 MHz, DMSO-D6) δ 9.30 (s, 1H), 9.14 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.63-7.54 (m, 2H), 7.22 (tt, J = 9.3, 2.2 Hz, 1H), 6.78-6.66 (m, 2H), 5.83 (s, 1H), 3.94 (t, J = 6.7 Hz, 3H), 3.78 (td, J = 6.6, 2.6 Hz, 2H), 3.47 (m, 5H), 3.29 (m, 2H), 3.23-3.14 (m, 2H), 2.20 (s, 3H), 1.04 (m, 3H) ppm. 585 406.66 0.67 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J = 2.3 Hz, 1H), 8.62 (dd, J = 4.8, 1.4 Hz, 1H), 8.38 (s, 1H), 8.01 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.47 (ddd, J = 8.3, 4.8, 0.6 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J = 5.5 Hz, 2H), 6.42 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.29 (d, J = 5.7 Hz, 2H), 3.37-3.16 (m, 4H), 2.65-2.47 (m, 4H), 2.35 (s, 3H), 1.43 (s, 3H) ppm. 586 453.41 0.68 1H NMR (300 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.66-7.53 (m, 2H), 7.22 (tt, J = 9.3, 2.3 Hz, 1H), 6.78 (s, 1H), 6.67 (s, 1H), 5.83 (s, 1H), 4.92 (s, 2H), 4.20 (s, 2H), 3.94 (t, J = 6.6 Hz, 2H), 3.59 (m, 3H), 3.54-3.44 (m, 2H), 3.22 (s, 2H), 2.60 (m, 2H), 2.19 (s, 3H) ppm. 587 445.3 0.6 1H NMR (400 MHz, DMSO-D6) δ 9.18 (s, 1H), 8.96 (d, J = 1.3 Hz, 1H), 7.68-7.53 (m, 3H), 7.26 (tt, J = 9.2, 2.2 Hz, 1H), 6.41 (dd, J = 5.5, 2.8 Hz, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.49-3.41 (m, 1H), 3.17-3.06 (m, 4H), 2.44-2.37 (m, 4H), 2.19 (d, J = 1.8 Hz, 3H) ppm. 588 363.27 0.69 1H NMR (300 MHz, MeOD) δ 8.57 (s, 1H), 7.80 (d, J = 7.7 Hz, 3H), 7.52 (dd, J = 10.6, 5.1 Hz, 2H), 7.43-7.32 (m, 1H), 6.93-6.84 (m, 2H), 6.73 (s, 1H), 2.41-2.26 (m, 6H) ppm. 589 482.87 2.57 1H NMR (300 MHz, DMSO-D6) δ 9.9 (s, 1H), 9.24 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.41-7.20 (m, 2H), 6.98 (s, 1H), 3.72-3.35 (m, 10H), 3.15-2.98 (m, 1H), 2.34 (s, 3H), 2.02 (d, J = 51.9 Hz, 4H) ppm. 590 442.28 0.61 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.66 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.47-7.40 (m, 1H), 7.35-7.27 (m, 2H), 6.86 (s, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.41 (t, J = 1.7 Hz, 1H), 4.70-4.58 (m, 4H), 4.46 (tt, J = 8.9, 4.1 Hz, 1H), 3.55 (p, J = 6.5 Hz, 1H), 3.09-2.97 (m, 1H), 2.66 (dt, J = 10.5, 4.0 Hz, 1H), 2.34 (s, 3H), 2.22 (dp, J = 13.4, 4.6 Hz, 1H), 2.04-1.85 (m, 3H), 1.74 (ddt, J = 11.0, 7.0, 3.8 Hz, 1H), 1.53 (tdd, J = 12.1, 9.7, 4.3 Hz, 1H) ppm. 591 485 0.7 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 7.9, 2.2 Hz, 2H), 6.87-6.72 (m, 1H), 6.55 (s, 1H), 6.24 (d, J = 2.2 Hz, 1H), 4.70 (p, J = 6.4 Hz, 4H), 4.47 (dt, J = 12.1, 6.0 Hz, 1H), 3.68-3.50 (m, 1H), 3.35-3.20 (m, 4H), 2.65-2.46 (m, 4H), 2.13 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H) ppm. 592 402.25 0.64 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.74-7.65 (m, 2H), 7.63-7.45 (m, 3H), 7.40 (d, J = 1.2 Hz, 1H), 7.32 (t, J = 2.1 Hz, 1H), 6.88 (s, 1H), 6.78 (d, J = 0.9 Hz, 1H), 4.71 (dt, J = 14.5, 6.4 Hz, 4H), 3.64-3.52 (m, 1H), 3.37-3.25 (m, 4H), 2.61-2.44 (m, 4H) ppm. 593 483.91 2.39 1H NMR (300 MHz, DMSO-D6) δ 10.99 (s, 1H), 9.45 (s, 1H), 9.18 (s, 1H), 7.68-7.58 (m, 2H), 7.34-7.20 (m, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.43 (s, 1H), 5.06 (s, 8H), 4.03 (s, 1H), 3.80 (s, 3H), 3.67 (s, 4H), 3.18 (s, 2H), 2.26 (s, 3H) ppm. 594 413 0.66 1H NMR (400 MHz, Acetone-D6) δ 8.90 (s, 1H), 8.61 (s, 1H), 7.74 (dd, J = 8.2, 1.2 Hz, 1H), 7.68 (dt, J = 10.3, 2.3 Hz, 1H), 7.59 (td, J = 8.2, 6.3 Hz, 1H), 7.19-7.07 (m, 3H), 6.29 (dt, J = 12.5, 2.2 Hz, 1H), 4.61 (t, J = 6.5 Hz, 2H), 4.54 (t, J = 6.1 Hz, 2H), 3.59-3.42 (m, 1H), 3.38-3.14 (m, 4H), 2.59-2.37 (m, 4H) ppm. 595 441.31 0.6 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.92 (s, 1H), 7.78 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.66-7.53 (m, 1H), 7.47 (d, J = 7.7 Hz, 1H), 6.73 (ddd, J = 56.2, 32.2, 18.0 Hz, 4H), 5.96 (s, 1H), 4.02 (t, J = 7.0 Hz, 2H), 3.77 (dd, J = 10.9, 5.8 Hz, 6H), 3.45-3.29 (m, 1H), 2.47 (s, 4H), 2.32 (s, 3H) ppm. 596 441.67 0.68 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.39 (s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 6.89-6.75 (m, 2H), 6.70 (s, 1H), 4.75-4.53 (m, 4H), 3.62-3.44 (m, 3H), 2.59 (s, 4H), 2.40 (d, J = 10.4 Hz, 7H) ppm. 597 443.34 0.63 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.79 (dd, J = 6.3, 2.7 Hz, 1H), 7.62-7.48 (m, 1H), 7.35-7.23 (m, 1H), 7.12 (m, 1H), 6.79 (s, 1H), 6.68 (s, 1H), 6.42 (s, 1H), 4.72 (p, J = 6.3 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.39-3.24 (m, 4H), 2.59-2.47 (m, 4H), 2.35 (s, 3H) ppm. 598 397 0.59 1H NMR (400 MHz, CDCl3) δ 9.18 (d, J = 1.2 Hz, 1H), 8.92 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.47-8.31 (m, 1H), 7.26 (s, 1H), 6.90 (dd, J = 14.6, 12.5 Hz, 3H), 6.28 (d, J = 11.9 Hz, 1H), 4.70 (dt, J = 15.4, 6.4 Hz, 4H), 3.67-3.51 (m, 1H), 3.41-3.23 (m, 3H), 2.67-2.40 (m, 4H) ppm. 599 444.28 0.56 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.28-7.25 (m, 2H), 7.12 (d, J = 1.7 Hz, 1H), 6.80 (dddd, J = 8.6, 6.4, 4.4, 2.3 Hz, 1H), 5.82 (d, J = 1.7 Hz, 1H), 4.80-4.59 (m, 4H), 3.92 (s, 3H), 3.65-3.49 (m, 5H), 2.51-2.40 (m, 4H) ppm. 600 405.26 0.63 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.98 (s, 1H), 7.92 (dd, J = 7.4, 5.5 Hz, 2H), 7.71-7.56 (m, 2H), 7.25 (s, 1H), 5.90 (s, 1H), 5.08 (d, J = 7.1 Hz, 1H), 4.36 (dtt, J = 10.5, 7.0, 3.4 Hz, 1H), 4.10-3.95 (m, 2H), 3.88 (td, J = 8.4, 5.4 Hz, 1H), 3.75 (dd, J = 9.1, 3.2 Hz, 1H), 2.34 (d, J = 6.1 Hz, 3H), 2.29 (dt, J = 12.8, 4.9 Hz, 1H), 1.91 (dddd, J = 12.7, 7.6, 5.4, 3.6 Hz, 1H) ppm. 601 482.22 0.66 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.61 (s, 1H), 7.42 (s, 1H), 7.27 (dd, J = 7.7, 2.2 Hz, 2H), 6.84 (ddd, J = 8.7, 5.4, 2.2 Hz, 1H), 6.12 (s, 1H), 4.16-4.06 (m, 2H), 3.93 (dd, J = 8.4, 5.3 Hz, 2H), 3.82-3.73 (m, 4H), 3.36 (dt, J = 12.2, 6.1 Hz, 1H), 2.47 (s, 4H) ppm. 602 455.4 0.69 1H NMR (300 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.65-7.53 (m, 2H), 7.23 (ttt, J = 9.3, 5.8, 2.3 Hz, 1H), 6.75 (s, 1H), 6.68 (s, 1H), 5.82 (s, 1H), 3.90 (t, J = 7.0 Hz, 2H), 3.66-3.57 (m, 2H), 3.57-3.48 (m, 2H), 3.21 (m, 1H), 2.27 (m, 2H), 2.19 (s, 3H), 2.13 (s, 2H), 1.16 (s, 6H) ppm. 603 1H NMR (400 MHz, DMSO-D6) δ 9.72 (s, 1H), 9.23 (s, 1H), 9.14 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 2.5, 1.4 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 6.74 (s, 1H), 3.65 (d, J = 8.5 Hz, 1H), 3.51 (d, J = 8.5 Hz, 1H), 2.32 (s, 3H), 1.68 (s, 3H) ppm. 604 361.12 0.72 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.83 (s, 1H), 7.75-7.65 (m, 3H), 7.50 (dd, J = 10.7, 5.1 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 13.6 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.09 (t, J = 7.3 Hz, 2H), 2.38 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H) ppm. 605 397.17 0.82 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.17 (t, J = 2.2 Hz, 1H), 6.89 (d, J = 1.7 Hz, 1H), 6.80 (tt, J = 8.7, 2.3 Hz, 1H), 6.51 (t, J = 1.7 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 5.13 (s, 2H), 3.94 (s, 3H), 2.37 (s, 3H) ppm. 606 409 0.65 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.74-7.53 (m, 2H), 7.24-7.09 (m, 2H), 6.67 (s, 1H), 6.64-6.48 (m, 2H), 5.93 (s, 1H), 3.97 (t, J = 7.0 Hz, 2H), 3.74 (t, J = 4.8 Hz, 6H), 3.45-3.25 (m, 1H), 2.46 (d, J = 4.3 Hz, 4H), 2.30 (s, 3H) ppm. 607 439.65 0.65 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.66-7.52 (m, 2H), 7.49-7.41 (m, 1H), 7.40-7.29 (m, 2H), 6.46 (d, J = 0.8 Hz, 1H), 4.70 (dt, J = 13.2, 6.4 Hz, 4H), 3.69-3.50 (m, 5H), 2.55-2.35 (m, 4H) ppm. 608 347.17 0.84 1H NMR (300 MHz, MeOD) δ 8.58 (s, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.56 (s, 1H), 7.54 (s, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.47 (t, J = 2.1 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 1.2 Hz, 1H), 3.97-3.81 (m, 4H), 3.31-3.15 (m, 4H) ppm. 609 406 0.63 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.41 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.93-7.81 (m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.23 (ddd, J = 7.3, 4.9, 1.1 Hz, 1H), 7.00 (t, J = 1.9 Hz, 1H), 6.71 (s, 1H), 6.56 (s, 1H), 6.16 (s, 1H), 4.65 (t, J = 6.5 Hz, 2H), 4.58 (t, J = 6.2 Hz, 2H), 3.76-3.65 (m, 1H), 3.61 (dt, J = 12.9, 5.6 Hz, 4H), 2.70-2.55 (m, 2H), 2.53-2.35 (m, 2H), 2.31 (s, 3H), 2.14-1.96 (m, 2H) ppm. 610 476.32 0.58 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.90 (s, 1H), 7.84-7.74 (m, 1H), 7.61-7.49 (m, 2H), 7.08 (d, J = 1.7 Hz, 1H), 5.73 (d, J = 1.7 Hz, 1H), 4.62 (p, J = 6.4 Hz, 4H), 3.83 (s, 3H), 3.54-3.37 (m, 5H), 2.37 (dd, J = 14.3, 9.2 Hz, 4H) ppm. 611 1H NMR (400 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.19 (s, 1H), 7.71-7.60 (m, 3H), 7.29-7.20 (m, 2H), 6.73 (s, 1H), 3.69 (d, J = 8.8 Hz, 1H), 3.60 (d, J = 8.8 Hz, 1H), 2.77 (s, 3H), 2.31 (s, 3H), 1.68 (s, 3H) ppm. 612 432.33 0.57 1H NMR (300 MHz, DMSO-D6) δ 9.93 (s, 1H), 9.21 (s, 1H), 7.69-7.53 (m, 2H), 7.35-7.21 (m, 1H), 6.92 (s, 1H), 5.59 (d, J = 1.4 Hz, 1H), 4.03 (t, J = 7.6 Hz, 2H), 3.81 (dd, J = 8.2, 5.0 Hz, 2H), 3.61 (s, 4H), 3.33-3.26 (m, 1H), 2.37 (s, 4H) ppm. 613 400.19 0.8 1H NMR (300 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.19 (s, 1H), 7.67 (dd, J = 6.7, 4.4 Hz, 3H), 7.25 (dd, J = 10.5, 8.2 Hz, 2H), 6.73 (s, 1H), 3.70 (d, J = 8.8 Hz, 1H), 3.59 (d, J = 8.8 Hz, 1H), 2.77 (s, 3H), 2.31 (s, 3H), 1.68 (s, 3H) ppm. 614 373.22 0.6 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.92 (s, 1H), 7.37-7.25 (m, 3H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 5.90 (s, 1H), 5.08 (s, 1H), 4.41-4.28 (m, 1H), 4.00 (ddd, J = 14.7, 11.1, 6.5 Hz, 2H), 3.88 (td, J = 8.4, 5.4 Hz, 1H), 3.74 (dd, J = 9.1, 3.2 Hz, 1H), 2.34 (s, 3H), 2.33-2.20 (m, 1H), 1.91 (dddd, J = 12.7, 7.5, 5.4, 3.6 Hz, 1H) ppm. 615 387.18 0.86 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.45 (ddd, J = 10.8, 6.8, 2.6 Hz, 1H), 7.32-7.23 (m, 1H), 7.18 (dd, J = 9.4, 8.2 Hz, 1H), 6.99 (s, 1H), 6.72 (s, 1H), 6.62 (s, 1H), 6.29 (d, J = 2.2 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 4.34 (d, J = 5.9 Hz, 2H), 3.94 (s, 2H), 2.22 (s, 3H), 1.33 (s, 3H) ppm. 616 428.62 0.57 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.83 (tt, J = 8.8, 2.3 Hz, 2H), 6.54 (s, 1H), 6.49 (s, 1H), 4.15 (t, J = 7.4 Hz, 2H), 3.99-3.90 (m, 2H), 3.82-3.72 (m, 4H), 3.41-3.30 (m, 1H), 2.48 (s, 4H), 2.42 (s, 3H) ppm. 617 443.42 0.69 1H NMR (300 MHz, DMSO-D6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.60 (m, 2H), 7.23 (ttt, J = 9.2, 5.8, 2.3 Hz, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 5.82 (s, 1H), 4.78 (m, 0.5H), 4.62 (m, 0.5H), 3.91 (t, J = 6.9 Hz, 2H), 3.58-3.48 (m, 2H), 3.28-3.18 (m, 1H), 2.45 (m, 2H), 2.26 (m, 2H), 2.19 (s, 3H), 1.81 (m, 4H) ppm. 618 455.4 0.7 1H NMR (300 MHz, DMSO-D6) δ 9.34 (s, 1H), 9.15 (s, 1H), 7.66-7.54 (m, 2H), 7.25 (tt, J = 9.2, 2.2 Hz, 1H), 6.76 (s, 1H), 6.68 (s, 1H), 5.81 (s, 1H), 3.89 (t, J = 7.0 Hz, 2H), 3.62-3.47 (m, 4H), 3.29-3.16 (m, 1H), 2.71 (d, J = 10.6 Hz, 2H), 2.19 (s, 3H), 1.58 (t, J = 10.6 Hz, 2H), 1.06 (d, J = 6.2 Hz, 6H) ppm. 619 415.25 0.63 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.28 (dd, J = 7.4, 2.6 Hz, 2H), 7.24 (s, 1H), 7.15 (s, 1H), 6.80 (tt, J = 8.7, 2.3 Hz, 1H), 6.15 (s, 1H), 4.32 (d, J = 13.0 Hz, 2H), 3.37 (s, 3H), 3.27 (d, J = 6.2 Hz, 2H), 2.81 (td, J = 12.7, 2.3 Hz, 2H), 2.34 (s, 3H), 1.85 (ddd, J = 17.3, 9.8, 2.4 Hz, 3H), 1.38-1.21 (m, 2H) ppm. 620 442.37 0.62 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.33-7.30 (m, 3H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 6.75 (dd, J = 4.5, 2.7 Hz, 2H), 6.42 (t, J = 1.7 Hz, 1H), 4.63 (q, J = 6.4 Hz, 4H), 4.47 (tt, J = 8.9, 4.1 Hz, 1H), 3.56 (p, J = 6.5 Hz, 1H), 3.10-2.99 (m, 1H), 2.66 (dd, J = 11.1, 4.1 Hz, 1H), 2.34 (s, 3H), 2.22 (td, J = 11.3, 10.1, 5.1 Hz, 1H), 2.06-1.86 (m, 3H), 1.79-1.66 (m, 1H), 1.54 (tdd, J = 12.1, 9.7, 4.2 Hz, 1H) ppm. 621 480.24 0.65 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.61-7.50 (m, 2H), 7.48 (s, 1H), 7.44 (dd, J = 9.0, 2.4 Hz, 1H), 7.35 (s, 1H), 6.60 (t, J = 56.1 Hz, 1H), 6.39 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.67-3.60 (m, 4H), 3.55 (p, J = 6.4 Hz, 1H), 2.45 (t, J = 5.1 Hz, 4H), 2.03 (s, 3H) ppm. 622 408 0.65 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.72-7.58 (m, 2H), 7.19 (t, J = 8.6 Hz, 2H), 7.07 (s, 1H), 6.80 (s, 1H), 6.64 (s, 1H), 6.39 (s, 1H), 4.82-4.60 (m, 4H), 3.56 (p, J = 6.3 Hz, 1H), 3.37-3.16 (m, 4H), 2.62-2.40 (m, 4H), 2.33 (s, 3H) ppm. 623 428.28 0.76 1H NMR (300 MHz, MeOD) δ 8.85 (s, 1H), 7.62-7.40 (m, 3H), 7.26 (s, 1H), 6.93 (tt, J = 9.0, 2.2 Hz, 1H), 6.76 (s, 1H), 4.77-4.64 (m, 3H), 4.54 (dd, J = 10.3, 2.1 Hz, 1H), 4.04 (dd, J = 11.5, 2.0 Hz, 1H), 3.85 (td, J = 11.5, 2.3 Hz, 1H), 3.55 (dd, J = 12.7, 6.2 Hz, 1H), 2.86 (d, J = 11.4 Hz, 1H), 2.75 (d, J = 11.4 Hz, 1H), 2.33 (s, 3H), 2.22-1.93 (m, 2H), 1.20 (dd, J = 23.1, 9.8 Hz, 1H) ppm. 624 439.25 0.6 1H NMR (400 MHz, DMSO-D6) δ 9.17 (s, 1H), 8.97 (s, 1H), 7.74 (dd, J = 12.4, 2.6 Hz, 1H), 7.64-7.56 (m, 1H), 7.35 (t, J = 9.1 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.86 (s, 1H), 6.29 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.45 (p, J = 6.3 Hz, 1H), 3.14 (t, J = 4.9 Hz, 4H), 2.41 (d, J = 9.8 Hz, 1H), 2.41 (s, 3H), 2.22 (s, 3H) ppm. 625 490.37 0.6 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.91 (s, 1H), 7.80 (dd, J = 5.4, 3.4 Hz, 1H), 7.62-7.47 (m, 2H), 7.26 (s, 1H), 6.22 (s, 1H), 4.71-4.55 (m, 4H), 4.39 (s, 2H), 3.61-3.50 (m, 4H), 3.48-3.41 (m, 1H), 3.39 (s, 3H), 2.45-2.29 (m, 4H) ppm. 626 428.28 0.78 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.58 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.44-7.37 (m, 1H), 7.32 (dd, J = 9.4, 8.2 Hz, 1H), 7.19 (t, J = 2.2 Hz, 1H), 7.05 (s, 1H), 6.81 (d, J = 1.7 Hz, 1H), 6.40 (t, J = 1.7 Hz, 1H), 4.58 (tt, J = 6.8, 3.5 Hz, 1H), 3.84 (ddd, J = 12.5, 8.1, 3.8 Hz, 1H), 3.74 (ddd, J = 13.6, 8.1, 3.7 Hz, 1H), 3.64 (ddd, J = 13.4, 7.1, 4.0 Hz, 1H), 3.42 (ddd, J = 13.6, 7.2, 3.9 Hz, 1H), 2.34 (s, 3H), 2.15 (s, 3H), 2.05-1.80 (m, 4H) ppm. 627 401.3 0.9 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 5.2 Hz, 1H), 7.60 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.47-7.39 (m, 1H), 7.36-7.31 (m, 1H), 7.15-7.02 (m, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.73-6.59 (m, 1H), 6.39 (d, J = 1.9 Hz, 1H), 4.03 (td, J = 11.4, 4.5 Hz, 2H), 3.87 (d, J = 6.4 Hz, 2H), 3.48 (td, J = 11.9, 2.3 Hz, 2H), 2.36 (d, J = 0.6 Hz, 3H), 1.80 (dd, J = 13.0, 3.7 Hz, 2H), 1.49 (qd, J = 12.2, 4.7 Hz, 2H) ppm. 628 384.3 0.86 1H NMR (300 MHz, DMSO-D6) δ 9.24 (s, 1H), 9.14 (s, 1H), 7.65-7.52 (m, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.90-6.82 (m, 1H), 6.69 (s, 1H), 6.02 (s, 1H), 4.61 (s, 1H), 4.43 (s, 1H), 3.81-3.68 (m, 2H), 3.50 (dd, J = 9.1, 1.6 Hz, 1H), 2.98 (d, J = 9.2 Hz, 1H), 2.21 (s, 3H), 1.97-1.78 (m, 2H) ppm. 629 442.33 0.75 1H NMR (300 MHz, DMSO-D6) δ 9.51 (s, 1H), 9.18 (s, 1H), 8.15 (s, 1H), 7.68-7.60 (m, 2H), 7.56 (d, J = 1.8 Hz, 1H), 7.35-7.18 (m, 2H), 6.70 (d, J = 1.7 Hz, 1H), 4.67-4.50 (m, 3H), 4.50-4.34 (m, 2H), 3.75 (dd, J = 11.2, 3.1 Hz, 1H), 3.64 (t, J = 7.1 Hz, 1H), 3.32 (t, J = 10.8 Hz, 1H), 2.73 (d, J = 2.2 Hz, 1H), 2.29 (s, 4H), 1.90 (t, J = 10.8 Hz, 1H), 0.79 (d, J = 6.4 Hz, 3H) ppm. 630 459.26 0.64 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 8.00 (dd, J = 7.7, 1.8 Hz, 1H), 7.30 (s, 1H), 7.27 (d, J = 2.2 Hz, 1H), 6.97 (d, J = 3.8 Hz, 1H), 6.82 (tt, J = 8.7, 2.3 Hz, 1H), 6.75 (d, J = 4.6 Hz, 1H), 4.74-4.56 (m, 4H), 3.62 (d, J = 1.2 Hz, 2H), 3.59-3.46 (m, 1H), 2.60 (s, 4H), 2.40 (s, 7H) ppm. 631 369.22 0.62 1H NMR (400 MHz, DMSO-D6) δ 9.69 (s, 1H), 9.21 (s, 1H), 7.67 (dd, J = 8.6, 2.2 Hz, 2H), 7.55 (s, 1H), 7.32-7.20 (m, 1H), 6.84 (s, 1H), 6.76 (s, 1H), 3.44-3.40 (m, 1H), 3.37-3.30 (m, 2H), 2.92 (t, J = 5.7 Hz, 1H), 2.45-2.41 (m, 2H), 2.33 (s, 3H) ppm. 632 442.32 0.62 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.65 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.50-7.37 (m, 1H), 7.34-7.29 (m, 1H), 7.28 (d, J = 2.0 Hz, 1H), 6.88 (s, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.41 (t, J = 1.7 Hz, 1H), 4.70-4.58 (m, 4H), 4.46 (tt, J = 8.9, 4.1 Hz, 1H), 3.61-3.49 (m, 1H), 3.09-3.00 (m, 1H), 2.66 (dt, J = 10.8, 4.0 Hz, 1H), 2.34 (s, 3H), 2.21 (dp, J = 12.2, 3.9 Hz, 1H), 2.06-1.84 (m, 3H), 1.71 (tdd, J = 14.7, 7.7, 3.9 Hz, 1H), 1.53 (tdd, J = 12.5, 9.5, 4.2 Hz, 1H) ppm. 633 441.67 0.68 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.58 (ddd, J = 10.9, 6.8, 2.5 Hz, 1H), 7.45-7.37 (m, 1H), 7.32 (dd, J = 9.3, 8.1 Hz, 1H), 7.07 (s, 1H), 6.81 (s, 1H), 6.65 (s, 1H), 6.43 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.37-3.17 (m, 4H), 2.66-2.47 (m, 4H), 2.35 (s, 3H), 1.44 (s, 3H) ppm. 634 425.36 0.69 1H NMR (300 MHz, DMSO-D6) δ 9.33 (s, 1H), 9.15 (s, 1H), 7.66-7.54 (m, 2H), 7.30-7.18 (m, 1H), 6.75 (s, 1H), 6.68 (s, 1H), 5.82 (s, 1H), 3.90 (t, J = 6.8 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.24-3.10 (m, 1H), 2.26 (m, 4H), 2.19 (s, 3H), 1.45 (m, 6H) ppm. 635 387.18 0.9 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.15-7.12 (m, 2H), 7.09 (t, J = 2.3 Hz, 1H), 6.65 (dddd, J = 8.6, 6.8, 4.8, 2.3 Hz, 3H), 6.28 (t, J = 1.6 Hz, 1H), 4.23 (tt, J = 7.7, 3.8 Hz, 1H), 3.93 (ddd, J = 11.4, 3.8, 1.7 Hz, 1H), 3.68 (dt, J = 11.3, 4.4 Hz, 1H), 3.49-3.36 (m, 2H), 2.20 (s, 3H), 2.05 (ddd, J = 9.7, 7.2, 4.6 Hz, 1H), 1.83-1.72 (m, 1H), 1.68 (ddd, J = 12.6, 8.6, 3.9 Hz, 1H), 1.56 (dtd, J = 13.6, 9.0, 4.7 Hz, 1H) ppm. 636 496.26 0.64 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.83 (dd, J = 5.4, 4.4 Hz, 2H), 7.70-7.57 (m, 2H), 7.53 (d, J = 7.7 Hz, 1H), 7.44 (s, 1H), 6.75 (t, J = 56.2 Hz, 1H), 6.11 (s, 1H), 4.16-4.05 (m, 2H), 3.93 (dd, J = 8.4, 5.3 Hz, 2H), 3.84-3.70 (m, 4H), 3.43-3.29 (m, 1H), 2.47 (s, 4H) ppm. 637 441 0.66 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.23 (dd, J = 7.9, 2.2 Hz, 2H), 7.08 (s, 1H), 6.77 (tt, J = 8.7, 2.3 Hz, 1H), 6.61 (s, 1H), 6.44 (s, 1H), 6.16 (s, 1H), 4.65 (t, J = 6.5 Hz, 2H), 4.58 (t, J = 6.2 Hz, 2H), 3.75-3.53 (m, 5H), 2.67-2.56 (m, 2H), 2.45-2.36 (m, 2H), 2.30 (s, 3H), 2.11-1.98 (m, 2H) ppm. 638 387.23 0.88 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.61 (ddd, J = 10.9, 6.8, 2.7 Hz, 1H), 7.42 (dp, J = 8.3, 1.9 Hz, 1H), 7.34-7.26 (m, 1H), 7.22 (t, J = 2.2 Hz, 1H), 6.96 (s, 1H), 6.80 (s, 1H), 6.41 (t, J = 1.6 Hz, 1H), 4.36 (tt, J = 7.7, 3.8 Hz, 1H), 4.08 (ddd, J = 11.3, 3.8, 1.6 Hz, 1H), 3.83 (dt, J = 11.3, 4.4 Hz, 1H), 3.63-3.49 (m, 2H), 2.34 (s, 3H), 2.19 (dq, J = 11.4, 4.5 Hz, 1H), 1.97-1.87 (m, 1H), 1.82 (ddt, J = 12.5, 8.3, 4.3 Hz, 1H), 1.76-1.63 (m, 1H) ppm. 639 458.32 0.55 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.88 (s, 1H), 7.83-7.77 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.26 (s, 1H), 7.19 (dd, J = 7.5, 1.7 Hz, 1H), 6.74 (t, J = 56.2 Hz, 1H), 5.81 (d, J = 1.7 Hz, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.92 (s, 3H), 3.63-3.49 (m, 5H), 2.52-2.39 (m, 4H) ppm. 640 407.21 0.93 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.60 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.45-7.39 (m, 1H), 7.33 (dd, J = 9.4, 8.2 Hz, 1H), 7.14 (t, J = 2.2 Hz, 1H), 6.84 (t, J = 1.8 Hz, 1H), 6.68 (s, 1H), 6.39 (t, J = 1.7 Hz, 1H), 4.12-3.92 (m, 2H), 2.87-2.61 (m, 3H), 2.61-2.45 (m, 2H), 2.36 (s, 3H) ppm. 641 485 0.71 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.31-7.17 (m, 3H), 7.12 (d, J = 2.1 Hz, 1H), 6.76 (tt, J = 8.7, 2.3 Hz, 1H), 6.54 (s, 1H), 5.77 (d, J = 2.1 Hz, 1H), 4.46 (dt, J = 12.1, 6.1 Hz, 1H), 4.00 (t, J = 6.9 Hz, 2H), 3.74 (dd, J = 8.2, 4.1 Hz, 6H), 3.42-3.24 (m, 1H), 2.53-2.37 (m, 4H), 2.11 (s, 3H), 1.33 (d, J = 6.1 Hz, 6H) ppm. 642 396 0.62 1H NMR (400 MHz, Acetone-D6) δ 8.99 (s, 1H), 8.66 (s, 1H), 8.48 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.05 (ddd, J = 8.2, 7.5, 1.8 Hz, 1H), 7.86 (dt, J = 8.2, 0.9 Hz, 1H), 7.39 (ddd, J = 7.4, 4.8, 1.0 Hz, 1H), 7.13 (tt, J = 4.1, 2.0 Hz, 2H), 6.30 (dt, J = 12.5, 2.2 Hz, 1H), 4.61 (t, J = 6.5 Hz, 2H), 4.55 (t, J = 6.1 Hz, 2H), 3.59-3.42 (m, 1H), 3.39-3.15 (m, 4H), 2.58-2.38 (m, 4H) ppm. 643 349.26 0.68 1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.84 (s, 1H), 7.70 (dd, J = 8.5, 1.1 Hz, 2H), 7.55-7.44 (m, 2H), 7.40-7.31 (m, 2H), 7.25 (s, 1H), 6.86 (s, 1H), 6.76 (s, 1H), 6.64 (d, J = 3.7 Hz, 1H), 2.38 (s, 3H) ppm. 644 429.27 0.84 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.56-7.36 (m, 4H), 7.02 (s, 1H), 6.68 (s, 1H), 6.20 (d, J = 1.9 Hz, 1H), 6.13 (t, J = 2.0 Hz, 1H), 4.42 (t, J = 5.2 Hz, 2H), 4.24 (t, J = 5.2 Hz, 2H), 2.19 (s, 3H) ppm. 645 465.3 0.7 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.90-7.78 (m, 2H), 7.64 (dd, J = 8.5, 7.7 Hz, 1H), 7.53 (t, J = 6.4 Hz, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 6.67 (dt, J = 66.6, 56.2 Hz, 3H), 6.40 (s, 1H), 4.37 (d, J = 13.2 Hz, 2H), 3.38 (s, 3H), 3.30 (t, J = 10.6 Hz, 2H), 2.88 (td, J = 12.8, 2.4 Hz, 2H), 1.86 (t, J = 10.9 Hz, 3H), 1.36-1.22 (m, 2H) ppm. 646 457.23 2.86 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.17 (d, J = 1.4 Hz, 1H), 7.01 (s, 1H), 6.69 (s, 1H), 6.51 (s, 1H), 6.33 (s, 1H), 4.62 (p, J = 6.4 Hz, 4H), 3.96 (t, J = 1.0 Hz, 3H), 3.50 (p, J = 6.4 Hz, 1H), 3.26-3.18 (m, 4H), 2.45 (dd, J = 6.0, 4.0 Hz, 4H), 2.26 (s, 3H) ppm. 647 427.31 0.62 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.58-7.50 (m, 1H), 7.45 (dt, J = 7.3, 3.6 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 6.99 (dt, J = 10.7, 2.1 Hz, 1H), 6.78 (dd, J = 5.7, 3.5 Hz, 2H), 6.26 (dt, J = 11.9, 2.2 Hz, 1H), 4.71 (dt, J = 13.1, 6.3 Hz, 4H), 3.58 (p, J = 6.5 Hz, 1H), 3.38-3.22 (m, 4H), 2.63-2.46 (m, 5H), 2.38 (d, J = 2.0 Hz, 3H) ppm. 648 387.14 0.88 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.01 (t, J = 2.2 Hz, 1H), 6.73-6.49 (m, 3H), 6.26 (t, J = 1.6 Hz, 1H), 3.90-3.73 (m, 4H), 3.71-3.62 (m, 1H), 3.60 (dd, J = 8.9, 5.3 Hz, 1H), 2.72-2.57 (m, 1H), 2.21 (s, 3H), 2.00 (dtd, J = 12.7, 8.1, 5.6 Hz, 1H), 1.63 (dtd, J = 12.8, 7.5, 5.9 Hz, 1H) ppm. 649 441.35 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.20 (s, 1H), 9.14 (s, 1H), 7.64 (dd, J = 8.6, 2.2 Hz, 2H), 7.32-7.18 (m, 1H), 6.84 (t, J = 2.0 Hz, 1H), 6.47 (s, 1H), 5.91-5.76 (m, 2H), 3.83-3.70 (m, 1H), 3.58 (t, J = 4.6 Hz, 4H), 2.95-2.78 (m, 1H), 2.35-2.18 (m, 6H), 2.14 (s, 3H), 2.02-1.94 (m, 1H) ppm. 650 512.37 0.51 1H NMR (400 MHz, DMSO-D6) δ 9.16 (s, 2H), 7.59 (dd, J = 8.6, 2.2 Hz, 2H), 7.28-7.20 (m, 1H), 6.84 (d, J = 1.4 Hz, 1H), 5.77 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.48-3.42 (m, 4H), 3.35-3.25 (m, 3H), 2.37 (m, 8H), 2.21 (s, 3H) ppm. 651 459.31 0.71 1H NMR (400 MHz, DMSO-D6) δ 9.32 (s, 1H), 9.23 (s, 1H), 8.17 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 5.81 (s, 1H), 3.90 (t, J = 7.0 Hz, 2H), 3.66-3.55 (m, 6H), 3.29-3.19 (m, 1H), 2.35 (s, 4H), 2.19 (s, 3H) ppm. 652 439.37 0.69 1H NMR (300 MHz, DMSO-D6) δ 9.30 (s, 1H), 9.14 (s, 1H), 7.60 (dd, J = 11.3, 4.8 Hz, 2H), 7.27-7.16 (m, 1H), 6.76 (s, 1H), 6.70 (s, 1H), 5.84 (s, 1H), 3.92 (m, 2H), 3.79-3.71 (m, 1H), 3.70-3.62 (m, 1H), 3.61-3.46 (m, 4H), 2.60 (d, J = 11.7 Hz, 2H), 2.38 (dd, J = 13.1, 7.2 Hz, 1H), 2.20 (s, 3H), 0.67 (m, 1H), 0.32 (dd, J = 13.2, 6.2 Hz, 1H) ppm. 653 471 0.69 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.31-7.15 (m, 2H), 6.95 (s, 1H), 6.87-6.72 (m, 2H), 6.69 (s, 1H), 6.13 (t, J = 1.9 Hz, 1H), 4.69 (p, J = 6.3 Hz, 4H), 4.57 (dt, J = 12.1, 6.0 Hz, 1H), 3.55 (p, J = 6.4 Hz, 1H), 3.35-3.20 (m, 4H), 2.55-2.41 (m, 4H), 1.38 (d, J = 6.1 Hz, 6H) ppm. 654 454.54 0.7 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.60 (d, J = 14.3 Hz, 1H), 7.47 (s, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 6.83 (tt, J = 8.7, 2.3 Hz, 1H), 6.45 (s, 1H), 3.78-3.46 (m, 4H), 2.69-2.55 (m, 4H), 2.50 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H) ppm. 655 1H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.18 (s, 1H), 7.71-7.61 (m, 3H), 7.60 (s, 1H), 7.30 (s, 1H), 7.24 (ddd, J = 9.3, 5.8, 2.3 Hz, 1H), 6.72 (s, 1H), 3.63 (d, J = 8.5 Hz, 1H), 3.50 (d, J = 8.5 Hz, 1H), 2.31 (s, 2H), 1.67 (s, 2H) ppm. 656 438.61 0.66 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.56 (ddd, J = 10.6, 6.7, 2.5 Hz, 1H), 7.42 (ddd, J = 6.4, 4.6, 3.1 Hz, 1H), 7.39-7.36 (m, 1H), 7.35-7.31 (m, 1H), 7.29 (s, 1H), 6.86 (s, 1H), 6.79 (dd, J = 2.1, 1.2 Hz, 1H), 4.71 (dt, J = 12.4, 6.4 Hz, 4H), 3.65-3.53 (m, 1H), 3.39-3.26 (m, 4H), 2.62-2.45 (m, 4H) ppm. 657 469.29 0.53 1H NMR (400 MHz, DMSO-D6) δ 9.25 (s, 1H), 9.15 (s, 1H), 7.58 (dd, J = 8.6, 2.2 Hz, 2H), 7.29-7.19 (m, 1H), 6.79 (d, J = 1.9 Hz, 2H), 6.06 (s, 1H), 3.18-3.04 (m, 8H), 2.47-2.40 (m, 8H), 2.22 (s, 6H) ppm. 658 386.13 0.75 1H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.19 (s, 1H), 7.65 (s, 3H), 7.61 (s, 1H), 7.30 (s, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.72 (s, 1H), 3.63 (d, J = 8.7 Hz, 1H), 3.50 (d, J = 8.9 Hz, 1H), 2.31 (s, 3H), 1.67 (s, 3H) ppm. 659 441 0.68 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.57 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.46-7.33 (m, 1H), 7.33-7.19 (m, 2H), 6.62 (dd, J = 8.6, 6.4 Hz, 3H), 5.95 (s, 1H), 4.01 (t, J = 6.9 Hz, 2H), 3.82 (t, J = 6.2 Hz, 2H), 3.77-3.72 (m, 2H), 3.71-3.61 (m, 2H), 3.63-3.52 (m, 1H), 2.63 (dd, J = 7.9, 3.6 Hz, 4H), 2.30 (s, 3H), 2.00-1.82 (m, 2H) ppm. 660 448.27 0.57 1H NMR (300 MHz, DMSO-D6) δ 10.03 (s, 1H), 9.21 (s, 1H), 7.62 (dd, J = 8.5, 2.1 Hz, 2H), 7.34-7.22 (m, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.00 (d, J = 1.6 Hz, 1H), 4.03 (t, J = 7.5 Hz, 2H), 3.81 (dd, J = 8.3, 5.0 Hz, 2H), 3.61 (s, 4H), 2.58-2.54 (m, 1H), 2.37 (s, 4H) ppm. 661 475.43 0.74 1H NMR (300 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.64-7.54 (m, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.72 (s, 2H), 5.82 (s, 1H), 3.94 (m, 2H), 3.56 (m, 3H), 3.19-3.06 (m, 4H), 2.83 (m, 4H), 2.20 (s, 3H) ppm. 662 475.24 0.64 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.03 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.69-7.57 (m, 2H), 6.92 (t, J = 2.0 Hz, 1H), 6.77 (s, 1H), 6.71 (t, J = 2.0 Hz, 1H), 6.17 (t, J = 2.1 Hz, 1H), 4.72 (dt, J = 15.5, 6.4 Hz, 4H), 3.86 (s, 3H), 3.59 (p, J = 6.4 Hz, 1H), 3.38-3.24 (m, 4H), 2.59-2.43 (m, 4H) ppm. 663 442.33 0.75 1H NMR (300 MHz, DMSO-D6) δ 9.51 (s, 1H), 9.18 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.70-7.57 (m, 2H), 7.22 (ddt, J = 18.4, 9.2, 2.0 Hz, 2H), 6.68 (s, 1H), 4.60-4.43 (m, 5H), 3.79 (ddd, J = 9.9, 6.1, 2.1 Hz, 1H), 3.41 (m, 1H), 2.85-2.69 (m, 2H), 2.50 (p, J = 1.9 Hz, 5H), 2.26 (s, 3H), 1.75 (t, J = 10.7 Hz, 1H), 1.63 (t, J = 10.5 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H) ppm. 664 471.64 0.61 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.51 (d, J = 0.8 Hz, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 6.83 (tt, J = 8.7, 2.3 Hz, 1H), 6.70 (d, J = 0.9 Hz, 1H), 6.27 (s, 1H), 4.79-4.57 (m, 4H), 3.74-3.61 (m, 4H), 3.60-3.49 (m, 1H), 3.05 (d, J = 4.9 Hz, 3H), 2.54-2.31 (m, 4H) ppm. 665 442.32 0.61 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.72-7.61 (m, 1H), 7.47-7.39 (m, 1H), 7.34-7.29 (m, 1H), 7.27 (d, J = 1.9 Hz, 1H), 6.92 (s, 1H), 6.76 (s, 1H), 6.41 (t, J = 1.6 Hz, 1H), 4.70-4.57 (m, 4H), 4.46 (tt, J = 8.9, 4.1 Hz, 1H), 3.56 (p, J = 6.5 Hz, 1H), 3.09-3.00 (m, 1H), 2.66 (dd, J = 10.9, 4.1 Hz, 1H), 2.34 (s, 3H), 2.21 (dp, J = 12.1, 3.9, 3.4 Hz, 1H), 2.05-1.93 (m, 2H), 1.89 (dp, J = 15.6, 4.0 Hz, 1H), 1.72 (dtt, J = 17.4, 6.8, 3.9 Hz, 1H), 1.59-1.47 (m, 1H) ppm. 666 349.15 0.62 1H NMR (300 MHz, DMSO-D6) δ 9.94 (s, 1H), 9.26 (s, 1H), 9.09 (s, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 6.94 (s, 1H), 3.92-3.63 (m, 4H), 3.20 (d, J = 4.6 Hz, 4H) ppm. 667 442.36 0.77 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.62-7.53 (m, 2H), 7.26 (dt, J = 6.0, 2.1 Hz, 3H), 6.88 (s, 1H), 6.78 (tt, J = 8.7, 2.3 Hz, 1H), 4.80-4.60 (m, 4H), 3.91-3.77 (m, 2H), 3.50 (dd, J = 13.4, 6.9 Hz, 1H), 2.91 (d, J = 11.5 Hz, 1H), 2.38 (d, J = 23.7 Hz, 6H), 1.52 (s, 3H) ppm. 668 383.58 0.88 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H), 9.11 (s, 1H), 8.07-7.91 (m, 1H), 7.77-7.61 (m, 2H), 7.50 (s, 1H), 7.42 (s, 1H), 6.91 (s, 1H), 3.87-3.69 (m, 4H), 3.23-3.09 (m, 4H) ppm. 669 374.25 0.83 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.74-7.64 (m, 2H), 7.57-7.47 (m, 3H), 7.42 (s, 1H), 7.40-7.32 (m, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.69 (s, 1H), 6.62 (s, 1H), 6.22 (s, 1H), 5.12 (s, 1H), 4.53-4.36 (m, 1H), 2.29 (s, 3H), 1.50 (d, J = 6.7 Hz, 6H) ppm. 670 441.35 0.68 1H NMR (300 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.66-7.52 (m, 2H), 7.22 (tt, J = 9.2, 2.3 Hz, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 5.84 (s, 1H), 4.00 (m, 1H), 3.90 (m, 1H), 3.66 (d, J = 11.3 Hz, 1H), 3.53 (m, 5H), 3.21-3.10 (m, 1H), 2.64 (d, J = 11.4 Hz, 1H), 2.41 (m, 1H), 2.19 (s, 3H), 2.12 (m, 1H), 0.91 (d, J = 6.4 Hz, 3H) ppm. 671 419.23 0.9 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.88 (dt, J = 7.7, 1.9 Hz, 1H), 7.71-7.58 (m, 2H), 7.26 (t, J = 2.2 Hz, 1H), 6.83 (t, J = 1.6 Hz, 1H), 6.74 (s, 1H), 6.45 (t, J = 1.6 Hz, 1H), 4.68 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 5.9 Hz, 2H), 4.10 (s, 2H), 2.37 (s, 3H), 1.48 (s, 3H) ppm. 672 496.53 0.71 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.28-7.18 (m, 2H), 6.83 (tt, J = 8.7, 2.3 Hz, 1H), 6.44 (s, 1H), 4.05-3.90 (m, 2H), 3.83 (dd, J = 15.9, 8.1 Hz, 1H), 3.72 (dd, J = 8.6, 6.8 Hz, 1H), 3.62 (t, J = 5.1 Hz, 4H), 3.11-2.98 (m, 1H), 2.66 (dt, J = 10.5, 5.1 Hz, 2H), 2.59-2.46 (m, 2H), 2.18-2.03 (m, 1H), 1.93 (ddd, J = 15.6, 12.3, 8.2 Hz, 1H) ppm. 673 442.26 0.62 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.30 (s, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 6.5 Hz, 2H), 6.81 (tt, J = 8.7, 2.2 Hz, 1H), 6.13 (s, 1H), 3.98 (ddd, J = 15.2, 8.5, 5.7 Hz, 2H), 3.83 (dd, J = 15.9, 8.1 Hz, 1H), 3.72 (dd, J = 8.5, 6.9 Hz, 1H), 3.56 (t, J = 5.1 Hz, 4H), 3.09-2.97 (m, 1H), 2.66 (dt, J = 10.3, 5.1 Hz, 2H), 2.59-2.47 (m, 2H), 2.35 (s, 3H), 2.17-2.04 (m, 1H), 1.93 (ddd, J = 15.7, 12.2, 8.2 Hz, 1H) ppm. 674 427.54 0.97 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.64 (s, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 6.83 (tt, J = 8.7, 2.3 Hz, 1H), 6.44 (s, 1H), 3.90-3.78 (m, 4H), 3.63-3.50 (m, 4H) ppm. 675 417.3 3.84 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.86 (s, 1H), 7.26-7.18 (m, 3H), 6.83-6.66 (m, 2H), 3.88 (s, 3H), 3.82-3.67 (m, 4H), 3.60-3.40 (m, 4H) ppm. 676 347.32 0.7 1H NMR (300 MHz, MeOD + CDCl3) δ 8.47 (s, 1H), 7.91 (s, 1H), 7.81-7.72 (m, 2H), 7.66 (t, J = 1.8 Hz, 1H), 7.57-7.48 (m, 2H), 7.41-7.33 (m, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 3.84 (s, 3H), 2.37 (s, 3H) ppm. 677 387.14 0.88 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.03 (s, 1H), 6.74-6.63 (m, 2H), 6.59 (s, 1H), 6.30 (t, J = 1.7 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 4.35 (d, J = 5.9 Hz, 2H), 3.95 (s, 2H), 2.22 (s, 3H), 1.33 (s, 3H) ppm. 678 438.7 0.66 1H NMR (300 MHz, MeOD + CDCl3) δ 8.63 (s, 1H), 7.50 (t, J = 2.2 Hz, 1H), 7.43-7.29 (m, 3H), 6.84 (tt, J = 8.8, 2.3 Hz, 1H), 6.80-6.73 (m, 1H), 4.73 (dt, J = 12.5, 6.5 Hz, 4H), 3.67-3.54 (m, 1H), 3.34 (d, J = 5.3 Hz, 4H), 2.65-2.45 (m, 4H) ppm. 679 1H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.18 (s, 1H), 7.71-7.62 (m, 3H), 7.60 (s, 1H), 7.28 (d, J = 10.2 Hz, 1H), 7.27-7.20 (m, 1H), 6.72 (s, 1H), 3.63 (d, J = 8.8 Hz, 1H), 3.50 (d, J = 8.8 Hz, 1H), 2.31 (s, 3H), 1.67 (s, 3H) ppm. 680 496.22 0.7 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.96 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.73-7.59 (m, 2H), 7.51 (s, 1H), 7.35 (s, 1H), 6.60 (t, J = 56.2 Hz, 2H), 6.39 (s, 1H), 4.72 (dt, J = 14.4, 6.4 Hz, 4H), 3.71-3.61 (m, 3H), 3.61-3.48 (m, 1H), 2.50-2.38 (m, 3H) ppm. 681 409.18 0.87 1H NMR (300 MHz, DMSO-D6) δ 9.35 (s, 2H), 9.08 (s, 2H), 7.97 (s, 1H), 7.91 (d, J = 7.6 Hz, 4H), 7.49 (t, J = 7.9 Hz, 4H), 7.31 (t, J = 7.4 Hz, 2H), 6.92 (d, J = 1.4 Hz, 2H), 2.26 (s, 3H) ppm. 682 1H NMR (400 MHz, DMSO-D6) δ 9.72 (s, 1H), 9.23 (s, 1H), 9.14 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 2.5, 1.4 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 6.74 (s, 1H), 3.65 (d, J = 8.6 Hz, 1H), 3.51 (d, J = 8.7 Hz, 1H), 2.32 (s, 3H), 1.68 (s, 3H) ppm. 683 441.39 0.66 1H NMR (300 MHz, DMSO-D6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.64-7.52 (m, 2H), 7.29-7.15 (m, 1H), 6.73 (s, 1H), 6.69 (s, 1H), 5.82 (s, 1H), 3.54 (m, 8H), 2.38 (m, 4H), 2.19 (s, 3H), 1.33 (s, 3H) ppm. 684 447.48 0.57 1H NMR (300 MHz, CDCl3) δ 9.02 (d, J = 2.5 Hz, 1H), 8.65 (dd, J = 4.8, 1.4 Hz, 1H), 8.44 (s, 1H), 8.05 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.64 (s, 1H), 7.51 (dd, J = 8.3, 4.8 Hz, 1H), 7.43 (s, 1H), 6.45 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 3.72-3.61 (m, 4H), 3.60-3.51 (m, 1H), 2.53-2.38 (m, 4H) ppm. 685 478.16 0.69 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.49 (s, 1H), 7.33 (s, 1H), 7.28-7.22 (m, 2H), 6.82 (tt, J = 8.7, 2.2 Hz, 1H), 6.38 (s, 1H), 4.81-4.60 (m, 4H), 3.63 (dd, J = 11.4, 6.4 Hz, 4H), 3.55 (dd, J = 12.8, 6.4 Hz, 1H), 2.52-2.33 (m, 4H), 1.96 (t, J = 18.3 Hz, 3H) ppm. 686 362.28 3.74 1H NMR (300 MHz, DMSO-D6) δ 9.57 (s, 1H), 9.18 (s, 1H), 7.74-7.60 (m, 2H), 7.27 (ddd, J = 9.3, 5.8, 2.2 Hz, 1H), 6.77-6.59 (m, 3H), 5.84-5.73 (m, 1H), 4.84 (t, J = 6.0 Hz, 2H), 4.56-4.37 (m, 3H) ppm. 687 416.33 0.57 1H NMR (300 MHz, DMSO-D6) δ 9.38 (s, 1H), 9.25 (s, 1H), 8.05 (d, J = 10.5 Hz, 4H), 7.16 (s, 1H), 6.89 (s, 1H), 6.32 (s, 1H), 4.53 (dt, J = 25.3, 6.4 Hz, 4H), 3.45 (d, J = 6.5 Hz, 1H), 3.15 (d, J = 5.7 Hz, 4H), 2.41 (s, 4H), 2.23 (s, 3H) ppm. 688 401.08 0.69 689 387.26 0.6 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.87 (s, 1H), 7.85-7.81 (m, 1H), 7.67 (s, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.52 (t, J = 8.3 Hz, 1H), 7.24 (s, 1H), 6.75 (t, J = 56.2 Hz, 1H), 5.89 (s, 1H), 4.87 (d, J = 7.1 Hz, 1H), 4.37 (dtt, J = 10.6, 7.1, 3.5 Hz, 1H), 4.00 (dt, J = 14.5, 6.5 Hz, 2H), 3.88 (td, J = 8.4, 5.5 Hz, 1H), 3.74 (dd, J = 9.2, 3.3 Hz, 1H), 2.33 (s, 3H), 2.32-2.24 (m, 1H), 1.96-1.84 (m, 1H) ppm. 690 455.4 0.77 1H NMR (300 MHz, DMSO-D6) δ 9.37 (s, 1H), 9.16 (s, 1H), 7.61 (d, J = 6.4 Hz, 2H), 7.31-7.20 (m, 1H), 6.82 (d, J = 11.2 Hz, 1H), 6.67 (s, 1H), 5.83 (s, 1H), 4.01 (t, J = 7.1 Hz, 2H), 3.91-3.76 (m, 3H), 3.57 (d, J = 4.3 Hz, 4H), 3.47 (s, 2H), 2.90 (d, J = 14.9 Hz, 2H), 2.20 (s, 3H) ppm. 691 445.3 0.64 1H NMR (400 MHz, DMSO-D6) δ 9.17 (s, 1H), 8.86 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 2.2 Hz, 2H), 7.51 (d, J = 5.6 Hz, 1H), 7.26 (tt, J = 9.2, 2.3 Hz, 1H), 6.44 (d, J = 5.9 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.51-3.40 (m, 1H), 3.02 (s, 4H), 2.39 (s, 4H), 2.27 (s, 3H) ppm. 692 398.21 0.94 1H NMR (300 MHz, DMSO-D6) δ 9.27 (s, 1H), 9.14 (s, 1H), 7.65-7.54 (m, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 7.07 (s, 1H), 6.84 (s, 1H), 6.23 (s, 1H), 4.42 (m, 2H), 3.33 (d, J = 11.3 Hz, 2H), 2.83 (dd, J = 11.4, 2.3 Hz, 2H), 2.22 (s, 3H), 1.84 (m, 4H) ppm. 693 457.29 0.58 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.92 (s, 1H), 7.79 (dd, J = 8.1, 1.1 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 6.92-6.53 (m, 4H), 6.16 (t, J = 2.1 Hz, 1H), 4.72 (dt, J = 14.3, 6.4 Hz, 4H), 3.86 (s, 3H), 3.64-3.53 (m, 1H), 3.38-3.24 (m, 4H), 2.60-2.45 (m, 4H) ppm. 694 384.25 0.75 1H NMR (400 MHz, DMSO-D6) δ 9.30 (s, 1H), 9.15 (s, 1H), 7.61-7.51 (m, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.81 (m, 1H), 6.68 (s, 1H), 5.95 (s, 1H), 4.27 (d, J = 10.4 Hz, 2H), 4.20 (d, J = 6.0 Hz, 2H), 3.59 (d, J = 9.1 Hz, 2H), 2.66 (m, 1H), 2.21 (s, 3H), 1.86 (d, J = 7.9 Hz, 1H) ppm. 695 423.22 0.66 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.53-7.40 (m, 3H), 7.12 (s, 1H), 7.06 (ddd, J = 10.3, 5.7, 3.0 Hz, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 6.42 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.41-3.17 (m, 4H), 2.64-2.46 (m, 4H), 2.35 (s, 3H), 1.44 (s, 3H) ppm. 696 441.35 0.66 1H NMR (300 MHz, DMSO-D6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.65-7.51 (m, 2H), 7.22 (tt, J = 9.3, 2.2 Hz, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 5.82 (s, 1H), 3.89 (t, J = 6.9 Hz, 2H), 3.77 (d, J = 10.0 Hz, 1H), 3.58 (t, J = 6.0 Hz, 2H), 3.48 (m, 2H), 3.28-3.20 (m, 1H), 2.72 (d, J = 11.2 Hz, 1H), 2.64 (d, J = 10.4 Hz, 1H), 2.19 (s, 3H), 1.96 (td, J = 10.9, 8.2 Hz, 1H), 1.66 (t, J = 10.4 Hz, 1H), 1.06 (d, J = 6.2 Hz, 3H) ppm. 697 441.34 0.68 1H NMR (400 MHz, DMSO-D6) δ 9.13 (s, 1H), 8.25 (s, 1H), 7.62-7.49 (m, 2H), 7.33 (s, 1H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.56 (s, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.54-3.41 (m, 1H), 2.84 (s, 4H), 2.38 (br s, 4H), 2.26 (s, 3H), 2.14 (s, 3H) ppm. 698 397.17 0.81 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.42 (dd, J = 8.9, 2.1 Hz, 3H), 7.26 (d, J = 9.1 Hz, 1H), 7.18 (dd, J = 9.5, 8.2 Hz, 1H), 6.94 (s, 1H), 6.68 (s, 1H), 6.58 (s, 1H), 6.20 (d, J = 2.0 Hz, 1H), 6.13 (t, J = 2.1 Hz, 1H), 4.41 (t, J = 5.3 Hz, 2H), 4.23 (t, J = 5.3 Hz, 2H), 2.18 (s, 3H) ppm. 699 346 0.66 1H NMR (300 MHz, DMSO-D6) δ 11.58 (s, 1H), 9.10 (s, 1H), 9.03 (s, 1H), 8.04 (s, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.34 (t, J = 7.4 Hz, 1H), 6.65 (s, 2H), 5.75 (d, J = 1.3 Hz, 1H), 2.18 (s, 6H) ppm. 700 442.28 0.62 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.31 (dd, J = 7.8, 2.3 Hz, 2H), 7.06 (s, 1H), 6.84-6.74 (m, 2H), 6.42 (s, 1H), 4.63 (p, J = 6.4 Hz, 5H), 4.46 (tt, J = 8.9, 4.1 Hz, 1H), 3.56 (p, J = 6.5 Hz, 1H), 3.04 (dd, J = 10.8, 3.8 Hz, 1H), 2.66 (dd, J = 10.6, 4.3 Hz, 1H), 2.34 (s, 3H), 2.22 (dp, J = 14.0, 4.7 Hz, 1H), 2.05-1.85 (m, 4H), 1.81-1.64 (m, 1H), 1.61-1.46 (m, 1H) ppm. 701 553.43 0.56 1H NMR (400 MHz, DMSO-D6) δ 9.23 (s, 1H), 9.14 (s, 1H), 7.60-7.56 (m, 2H), 7.23 (m, 1H), 6.61 (s, 1H), 6.39 (s, 1H), 5.56 (s, 1H), 4.57 (t, J = 6.4 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 3.87 (m, 2H), 3.57 (m, 6H), 3.47-3.40 (m, 1H), 3.23 (s, 1H), 3.12 (s, 4H), 2.39 (s, 4H), 2.34 (s, 4H) ppm. 702 428.33 0.6 1H NMR (400 MHz, DMSO-D6) δ 9.37 (s, 1H), 9.18 (s, 1H), 7.69-7.59 (m, 2H), 7.26 (tt, J = 9.2, 2.3 Hz, 1H), 6.92 (s, 1H), 6.13 (s, 1H), 3.46 (s, 4H), 2.56 (dd, J = 13.0, 8.3 Hz, 4H), 2.22 (s, 3H), 1.04 (s, 9H) ppm. 703 373.23 0.86 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.32-7.21 (m, 2H), 7.14 (t, J = 2.3 Hz, 1H), 6.89-6.70 (m, 3H), 6.36 (t, J = 1.7 Hz, 1H), 5.06-4.93 (m, 1H), 4.10-3.87 (m, 4H), 2.35 (s, 3H), 2.32-2.17 (m, 2H) ppm. 704 391 0.64 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.74-7.60 (m, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 6.74 (s, 1H), 6.71-6.55 (m, 2H), 5.93 (s, 1H), 3.98 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 6.2 Hz, 6H), 3.45-3.23 (m, 1H), 2.46 (d, J = 4.2 Hz, 4H), 2.30 (s, 3H) ppm. 705 378.23 4.05 1H NMR (300 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.19 (s, 1H), 7.66 (dd, J = 8.5, 2.1 Hz, 2H), 7.28 (ddd, J = 9.3, 5.8, 2.3 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 6.82 (t, J = 1.8 Hz, 1H), 6.72 (d, J = 5.7 Hz, 1H), 6.00 (t, J = 1.8 Hz, 1H), 4.85 (t, J = 6.1 Hz, 2H), 4.57-4.38 (m, 3H) ppm. 706 407.21 0.95 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.29 (s, 2H), 7.16 (t, J = 2.2 Hz, 1H), 6.87-6.78 (m, 2H), 6.71 (s, 1H), 6.41 (t, J = 1.7 Hz, 1H), 4.10-4.01 (m, 2H), 2.77 (dddd, J = 13.5, 11.8, 10.0, 8.4 Hz, 3H), 2.61-2.45 (m, 2H), 2.36 (s, 3H) ppm. 707 439.27 0.62 1H NMR (400 MHz, DMSO-D6) δ 10.20 (s, 1H), 9.22 (s, 1H), 7.70-7.57 (m, 3H), 7.33-7.25 (m, 1H), 7.18 (d, J = 2.1 Hz, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 3.50-3.43 (m, 5H), 2.42-2.38 (m, 4H) ppm. 708 442.33 0.75 1H NMR (300 MHz, DMSO-D6) δ 9.45 (s, 1H), 9.11 (s, 1H), 7.63-7.51 (m, 3H), 7.25-7.11 (m, 2H), 6.70 (s, 1H), 4.54-4.38 (m, 3H), 4.33 (t, J = 6.0 Hz, 1H), 3.60 (dtd, J = 16.5, 8.0, 4.6 Hz, 2H), 3.27 (d, J = 6.4 Hz, 1H), 2.79 (d, J = 11.5 Hz, 1H), 2.24 (s, 4H), 2.19-1.98 (m, 2H), 1.28 (s, 3H) ppm. 709 427.29 0.67 1H NMR (400 MHz, DMSO-D6) δ 9.33 (s, 1H), 9.16 (s, 1H), 7.61 (dd, J = 8.6, 2.2 Hz, 2H), 7.25 (ddd, J = 9.3, 5.7, 2.3 Hz, 1H), 7.14 (s, 1H), 6.85 (s, 1H), 6.30 (s, 1H), 3.16-3.06 (m, 4H), 2.66-2.59 (m, 4H), 2.22 (s, 3H), 1.05 (s, 9H) ppm. 709 427.29 0.67 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.53-7.45 (m, 2H), 7.02 (s, 1H), 6.97-6.88 (m, 2H), 6.71 (s, 1H), 6.50 (s, 1H), 6.30 (s, 1H), 4.68-4.56 (m, 4H), 3.79 (s, 3H), 3.49 (p, J = 6.4 Hz, 1H), 3.24-3.17 (m, 4H), 2.47-2.40 (m, 4H), 2.25 (s, 3H) ppm. 711 413.34 3.37 1H NMR (300 MHz, DMSO-D6) δ 9.31 (s, 1H), 9.15 (s, 1H), 7.64-7.53 (m, 2H), 7.22 (tt, J = 9.2, 2.2 Hz, 1H), 6.79 (s, 1H), 6.70 (s, 1H), 5.84 (s, 1H), 4.02 (m, 2H), 3.82 (m, 3H), 2.90 (s, 3H), 2.84 (s, 3H), 2.20 (s, 3H) ppm. 712 448.56 0.63 1H NMR (300 MHz, CDCl3) δ 9.22 (d, J = 1.4 Hz, 1H), 8.97 (s, 1H), 8.61 (d, J = 2.5 Hz, 1H), 8.42 (dd, J = 2.5, 1.5 Hz, 1H), 7.67 (s, 1H), 7.47 (s, 1H), 6.47 (s, 1H), 4.79-4.63 (m, 4H), 3.73-3.63 (m, 4H), 3.56 (dt, J = 12.8, 6.4 Hz, 1H), 2.53-2.38 (m, 4H) ppm. 713 444.24 0.59 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.58 (ddd, J = 10.8, 6.8, 2.5 Hz, 1H), 7.46-7.37 (m, 1H), 7.33 (dd, J = 10.4, 7.0 Hz, 2H), 7.25 (s, 1H), 6.34 (s, 1H), 4.77-4.65 (m, 6H), 3.72-3.53 (m, 6H), 2.54-2.39 (m, 4H) ppm. 714 397.17 0.8 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.61 (ddd, J = 10.8, 6.8, 2.6 Hz, 1H), 7.48-7.41 (m, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 9.5, 8.3 Hz, 1H), 7.19 (t, J = 2.2 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.73 (s, 1H), 6.50 (t, J = 1.8 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 5.12 (s, 2H), 3.94 (s, 3H), 2.36 (s, 3H) ppm. 715 453.33 0.65 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.52-7.31 (m, 2H), 7.22 (t, J = 2.2 Hz, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 6.45 (s, 1H), 4.80-4.66 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.39-3.28 (m, 5H), 2.64 (q, J = 7.6 Hz, 2H), 2.59-2.49 (m, 5H), 2.43 (s, 3H), 1.28 (t, J = 7.6 Hz, 4H) ppm. 716 478.62 0.68 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 7.26 (d, J = 2.2 Hz, 2H), 6.90-6.76 (m, 1H), 6.51 (d, J = 56.2 Hz, 1H), 6.39 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.73-3.54 (m, 4H), 2.61-2.41 (m, 4H), 1.40 (s, 3H) ppm. 717 453.46 0.68 1H NMR (300 MHz, DMSO-D6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.59 (m, 2H), 7.22 (m, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 5.82 (s, 1H), 4.24 (m, 2H), 3.86 (t, J = 7.0 Hz, 2H), 3.56-3.46 (m, 2H), 3.26 (m, 1H), 2.54 (m, 2H), 2.19 (s, 3H), 2.12 (d, J = 9.4 Hz, 2H), 1.86-1.77 (m, 2H), 1.75-1.65 (m, 2H) ppm. 718 478.26 0.62 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.91-7.73 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.57-7.48 (m, 2H), 7.39 (d, J = 14.7 Hz, 1H), 6.91-6.43 (m, 2H), 6.39 (s, 1H), 4.71 (dq, J = 12.4, 6.4 Hz, 4H), 3.70-3.61 (m, 4H), 3.59-3.48 (m, 1H), 2.51-2.37 (m, 4H) ppm. 719 496.3 0.65 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.96 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.73-7.60 (m, 2H), 7.52 (s, 1H), 7.37 (s, 1H), 6.59 (t, J = 56.2 Hz, 1H), 6.06 (s, 1H), 4.12 (dd, J = 16.3, 8.5 Hz, 2H), 3.92 (dd, J = 8.3, 5.3 Hz, 2H), 3.83-3.72 (m, 4H), 3.35 (dt, J = 12.2, 6.1 Hz, 1H), 2.47 (s, 4H) ppm. 720 427.34 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.21 (s, 1H), 9.04 (s, 1H), 8.00-7.87 (m, 1H), 7.73-7.58 (m, 2H), 6.70 (s, 2H), 5.80 (s, 1H), 3.88 (t, J = 7.0 Hz, 2H), 3.64-3.52 (m, 6H), 3.28-3.20 (m, 1H), 2.35 (m, 4H), 2.19 (s, 3H) ppm. 721 409 0.63 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.45 (dt, J = 10.3, 2.6 Hz, 3H), 7.09-6.98 (m, 1H), 6.72 (s, 1H), 6.69-6.59 (m, 2H), 5.94 (s, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.75 (dd, J = 8.1, 4.3 Hz, 6H), 3.43-3.27 (m, 1H), 2.46 (d, J = 4.2 Hz, 4H), 2.30 (s, 3H) ppm. 722 398.35 0.79 1H NMR (300 MHz, DMSO-D6) δ 9.24 (s, 1H), 9.14 (s, 1H), 7.63-7.51 (m, 2H), 7.22 (tt, J = 9.2, 2.3 Hz, 1H), 7.06 (s, 1H), 6.75 (s, 1H), 6.24 (s, 1H), 4.05 (m, 2H), 3.77 (d, J = 10.6 Hz, 2H), 3.45 (d, J = 10.5 Hz, 2H), 2.22 (s, 3H), 1.97-1.86 (m, 4H) ppm. 723 447 0.68 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.35-7.14 (m, 1H), 6.89 (t, J = 1.9 Hz, 1H), 6.79 (tt, J = 8.7, 2.3 Hz, 1H), 6.65 (s, 1H-NH), 6.58 (t, J = 2.0 Hz, 1H), 6.09 (t, J = 1.9 Hz, 1H), 3.99 (t, J = 7.1 Hz, 2H), 3.76 (dd, J = 7.6, 5.3 Hz, 6H), 3.35 (dd, J = 12.7, 6.1 Hz, 1H), 2.45 (m, 4H) ppm. 724 414.29 0.88 1H NMR (300 MHz, DMSO-D6) δ 9.42 (s, 1H), 9.17 (s, 1H), 7.69-7.55 (m, 2H), 7.34-7.19 (m, 2H), 6.87 (s, 1H), 6.40 (s, 1H), 4.47 (dd, J = 21.6, 6.9 Hz, 4H), 3.78-3.68 (m, 2H), 3.08-2.99 (m, 2H), 2.25 (s, 3H) ppm. 725 469.3 0.56 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.92 (s, 1H), 7.79 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.26 (t, J = 2.0 Hz, 1H), 6.92-6.56 (m, 3H), 6.43 (s, 1H), 3.84 (d, J = 12.6 Hz, 2H), 3.80-3.72 (m, 4H), 2.80 (td, J = 12.3, 2.2 Hz, 2H), 2.66-2.57 (m, 4H), 2.43-2.34 (m, 1H), 2.34 (d, J = 4.3 Hz, 3H), 1.97 (d, J = 12.5 Hz, 2H), 1.70 (qd, J = 12.2, 3.9 Hz, 2H) ppm. 726 554.42 0.51 1H NMR (400 MHz, DMSO-D6) δ 9.19 (s, 1H), 9.16 (s, 1H), 7.59 (dd, J = 8.6, 2.2 Hz, 2H), 7.29-7.20 (m, 1H), 6.86 (d, J = 1.3 Hz, 1H), 5.78 (s, 1H), 4.57 (td, J = 6.5, 2.0 Hz, 4H), 4.48 (t, J = 6.0 Hz, 4H), 3.54-3.37 (m, 6H), 3.33-3.25 (m, 4H), 2.42-2.35 (m, 4H), 2.35-2.28 (m, 4H) ppm. 727 384.21 0.87 1H NMR (300 MHz, DMSO-D6) δ 9.23 (s, 1H), 9.14 (s, 1H), 7.65-7.51 (m, 2H), 7.22 (tt, J = 9.3, 2.3 Hz, 1H), 6.87 (s, 1H), 6.69 (s, 1H), 6.02 (s, 1H), 4.61 (m, 1H), 4.43 (m, 1H), 3.80-3.69 (m, 2H), 3.55-3.45 (m, 1H), 2.99 (d, J = 9.2 Hz, 1H), 1.94 (dd, J = 9.5, 1.7 Hz, 1H), 1.84 (d, J = 9.4 Hz, 1H) ppm. 728 464.16 0.68 1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.65 (s, 1H), 7.48 (dt, J = 4.2, 2.2 Hz, 2H), 7.44 (s, 1H), 7.39 (s, 1H), 7.15-7.02 (m, 1H), 6.44 (s, 1H), 4.71 (p, J = 6.4 Hz, 4H), 3.74-3.60 (m, 4H), 3.56 (dt, J = 12.8, 6.4 Hz, 2H), 2.57-2.38 (m, 4H) ppm. 729 451.26 0.74 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.41 (d, J = 7.7 Hz, 2H), 7.28-7.25 (m, 2H), 6.82 (tt, J = 8.7, 2.3 Hz, 1H), 6.59 (t, J = 56.2 Hz, 1H), 6.41 (s, 1H), 4.37 (d, J = 13.1 Hz, 2H), 3.38 (s, 3H), 3.28 (d, J = 6.2 Hz, 2H), 2.87 (td, J = 12.9, 2.4 Hz, 2H), 1.95-1.79 (m, 3H), 1.28 (qt, J = 14.7, 7.2 Hz, 2H) ppm. 730 441.39 0.68 1H NMR (300 MHz, DMSO-D6) δ 9.35 (s, 1H), 9.16 (s, 1H), 7.66-7.55 (m, 2H), 7.31-7.17 (m, 1H), 6.82 (s, 1H), 6.66 (s, 1H), 5.84 (s, 1H), 4.00 (t, J = 5.8 Hz, 1H), 3.90 (t, J = 5.9 Hz, 1H), 3.66 (d, J = 10.9 Hz, 1H), 3.60-3.44 (m, 5H), 3.16 (dd, J = 10.8, 8.1 Hz, 1H), 2.63 (d, J = 11.5 Hz, 1H), 2.40 (m, 1H), 2.19 (s, 3H), 2.11 (t, J = 8.3 Hz, 1H), 0.91 (d, J = 6.4 Hz, 3H) ppm. 731 386.24 0.58 1H NMR (400 MHz, DMSO-D6) δ 9.36 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J = 8.6, 2.2 Hz, 2H), 7.24 (tt, J = 9.3, 2.3 Hz, 1H), 6.94 (s, 1H), 6.15 (s, 1H), 3.47 (s, 4H), 2.36 (dd, J = 13.0, 8.3 Hz, 4H), 2.21 (s, 3H), 2.20 (s, 3H) ppm. 732 464.53 0.67 1H NMR (300 MHz, MeOD + CDCl3) δ 8.79 (s, 1H), 7.45 (dd, J = 7.0, 5.1 Hz, 3H), 6.87 (t, J = 8.7 Hz, 1H), 6.54 (d, J = 55.9 Hz, 1H), 6.08 (s, 1H), 4.14 (t, J = 7.6 Hz, 2H), 3.93 (dd, J = 8.3, 5.3 Hz, 2H), 3.87-3.65 (m, 4H), 3.38 (s, 1H), 2.51 (s, 4H) ppm. 733 448.31 0.59 1H NMR (400 MHz, DMSO-D6) δ 10.05 (s, 1H), 9.22 (s, 1H), 7.61 (d, J = 6.3 Hz, 3H), 7.46 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 10.3, 8.1 Hz, 2H), 6.53 (d, J = 1.9 Hz, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 3.47-3.42 (m, 1H), 3.40 (s, 4H), 2.38 (s, 4H) ppm. 734 430.37 0.6 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 8.03 (d, J = 1.1 Hz, 1H), 7.95-7.82 (m, 1H), 7.67-7.58 (m, 2H), 7.16 (t, J = 2.0 Hz, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 6.47 (s, 1H), 4.77-4.61 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.39-3.24 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 2.59-2.50 (m, 4H), 1.37-1.20 (m, 3H) ppm. 735 439.23 2.76 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.47 (dd, J = 11.7, 2.6 Hz, 1H), 7.36 (ddd, J = 8.8, 2.6, 1.6 Hz, 1H), 7.06 (t, J = 8.8 Hz, 1H), 6.71-6.61 (m, 2H), 5.94 (s, 1H), 3.97 (d, J = 16.7 Hz, 5H), 3.78-3.70 (m, 6H), 3.47-3.29 (m, 2H), 2.46 (t, J = 4.7 Hz, 4H), 2.29 (s, 3H) ppm. 736 455.31 0.61 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.93 (s, 1H), 7.78 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.67-7.54 (m, 1H), 7.47 (d, J = 7.7 Hz, 1H), 6.91-6.54 (m, 3H), 6.46 (s, 1H), 4.72 (dt, J = 13.0, 6.4 Hz, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.39-3.27 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.61-2.49 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 737 365.22 0.86 1H NMR (300 MHz, MeOD) δ 8.62 (s, 1H), 7.59-7.53 (m, 2H), 7.51-7.44 (m, 3H), 7.17-7.03 (m, 1H), 6.83-6.74 (m, 1H), 3.97-3.84 (m, 4H), 3.31-3.20 (m, 4H) ppm. 738 428.94 2.69 739 441.34 0.64 1H NMR (400 MHz, DMSO-D6) δ 9.27 (s, 1H), 9.15 (s, 1H), 7.61 (dd, J = 8.7, 2.2 Hz, 2H), 7.27-7.18 (m, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 3.97 (t, J = 6.9 Hz, 2H), 3.59 (t, J = 6.4 Hz, 6H), 3.21-3.12 (m, 1H), 2.33 (s, 4H), 2.16 (s, 3H), 1.97 (s, 3H) ppm. 740 442.57 0.62 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.21 (s, 2H), 6.81 (tt, J = 8.7, 2.2 Hz, 1H), 6.13 (s, 1H), 3.98 (ddd, J = 15.3, 8.7, 5.6 Hz, 2H), 3.83 (dd, J = 15.9, 8.1 Hz, 1H), 3.73 (d, J = 7.0 Hz, 1H), 3.56 (t, J = 5.1 Hz, 4H), 3.03 (p, J = 7.2 Hz, 1H), 2.75-2.60 (m, 2H), 2.60-2.47 (m, 2H), 2.36 (s, 3H), 2.17-2.04 (m, 1H), 1.93 (ddd, J = 15.9, 12.3, 8.2 Hz, 1H) ppm. 741 352.2 0.65 1H NMR (400 MHz, DMSO-D6) δ 9.73 (s, 1H), 9.23 (s, 1H), 9.14 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 6.74 (s, 1H), 3.65 (d, J = 8.9 Hz, 1H), 3.51 (d, J = 8.8 Hz, 1H), 2.32 (s, 3H), 1.68 (s, 3H) ppm. 742 439.46 0.67 1H NMR (300 MHz, DMSO-D6) δ 9.34 (s, 1H), 9.16 (s, 1H), 7.60 (dd, J = 8.7, 2.2 Hz, 2H), 7.30-7.18 (m, 1H), 6.76 (s, 1H), 6.70 (s, 1H), 5.84 (s, 1H), 4.47 (d, J = 6.1 Hz, 2H), 3.93 (m, 2H), 3.71 (m, 3H), 3.07 (d, J = 11.0 Hz, 2H), 2.86 (dd, J = 13.8, 6.4 Hz, 1H), 2.65 (d, J = 11.1 Hz, 2H), 2.20 (s, 3H), 2.17 (m, 1H) ppm. 743 402.03 0.91 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.41 (s, 1H), 7.28-7.25 (m, 2H), 6.86 (tt, J = 8.6, 2.3 Hz, 1H), 6.11-5.90 (m, 1H), 4.89 (s, 4H), 4.21 (d, J = 2.1 Hz, 4H) ppm. 744 371.24 0.61 1H NMR (400 MHz, DMSO-D6) δ 9.64 (s, 1H), 9.20 (s, 1H), 7.72-7.61 (m, 2H), 7.59 (s, 1H), 7.27 (tt, J = 9.3, 2.3 Hz, 1H), 6.61 (s, 1H), 3.01 (d, J = 12.0 Hz, 2H), 2.61-2.53 (m, 3H), 2.32 (s, 3H), 1.74 (d, J = 10.6 Hz, 2H), 1.58 (qd, J = 12.2, 3.9 Hz, 2H) ppm. 745 460.87 2.54 1H NMR (300 MHz, DMSO-D6) δ 9.28 (s, 1H), 9.15 (s, 1H), 7.65-7.54 (m, 2H), 7.30-7.14 (m, 2H), 6.80 (s, 1H), 6.31 (s, 1H), 3.57 (t, J = 12.4 Hz, 5H), 2.80 (t, J = 11.3 Hz, 2H), 2.35 (s, 1H), 2.22 (s, 3H), 1.74 (d, J = 13.5 Hz, 2H), 1.34 (t, J = 10.2 Hz, 2H) ppm. 746 453.46 0.68 1H NMR (300 MHz, DMSO-D6) δ 9.27 (s, 1H), 9.14 (s, 1H), 7.67-7.53 (m, 2H), 7.22 (tt, J = 9.3, 2.3 Hz, 1H), 6.76-6.65 (m, 2H), 5.80 (s, 1H), 3.91 (t, J = 6.7 Hz, 2H), 3.58-3.32 (m, 7H), 3.03 (m, 2H), 2.20 (s, 3H), 1.87-1.70 (m, 4H) ppm. 747 455.94 2.38 748 442.32 0.62 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.23-7.17 (m, 3H), 7.02 (s, 1H), 6.78-6.61 (m, 2H), 6.32 (d, J = 1.7 Hz, 1H), 4.52 (q, J = 6.7 Hz, 4H), 4.36 (tt, J = 8.8, 4.0 Hz, 1H), 3.46 (p, J = 6.5 Hz, 1H), 3.00-2.91 (m, 1H), 2.62-2.53 (m, 1H), 2.24 (s, 3H), 2.12 (dt, J = 13.2, 4.4 Hz, 1H), 1.95-1.75 (m, 3H), 1.63 (ddt, J = 20.8, 10.9, 3.2 Hz, 1H), 1.50-1.38 (m, 1H) ppm. 749 444.28 0.59 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.62-7.50 (m, 2H), 7.43 (dd, J = 8.9, 2.2 Hz, 1H), 7.22 (s, 1H), 7.19 (s, 1H), 6.13 (s, 1H), 4.78-4.63 (m, 4H), 3.72-3.47 (m, 5H), 2.45 (t, J = 5.0 Hz, 4H), 2.35 (s, 3H) ppm. 750 442.36 0.77 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.62 (s, 1H), 7.56 (t, J = 1.9 Hz, 1H), 7.26 (dt, J = 6.1, 2.2 Hz, 3H), 6.88 (s, 1H), 6.78 (tt, J = 8.7, 2.3 Hz, 1H), 4.80-4.69 (m, 1H), 4.72-4.60 (m, 3H), 3.88-3.80 (m, 2H), 3.50 (dd, J = 13.5, 7.1 Hz, 1H), 2.91 (d, J = 11.5 Hz, 1H), 2.38 (d, J = 23.6 Hz, 6H), 1.52 (s, 3H) ppm. 751 428.28 0.77 1H NMR (300 MHz, MeOD) δ 8.85 (s, 1H), 7.62-7.40 (m, 3H), 7.26 (s, 1H), 6.94 (ddd, J = 9.0, 5.6, 2.3 Hz, 1H), 6.76 (s, 1H), 4.67 (dt, J = 12.2, 6.7 Hz, 3H), 4.54 (dd, J = 10.3, 2.1 Hz, 1H), 4.04 (dd, J = 11.5, 2.0 Hz, 1H), 3.85 (td, J = 11.5, 2.4 Hz, 1H), 3.55 (dd, J = 12.7, 6.1 Hz, 1H), 2.86 (d, J = 11.5 Hz, 1H), 2.75 (d, J = 11.4 Hz, 1H), 2.33 (s, 3H), 2.24-1.96 (m, 2H), 1.29-1.11 (m, 1H) ppm. 752 442.47 0.69 1H NMR (300 MHz, DMSO-D6) δ 9.43 (s, 1H), 9.14 (s, 1H), 7.65-7.52 (m, 2H), 7.31-7.18 (m, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.17 (s, 1H), 3.58 (t, J = 4.6 Hz, 4H), 2.97-2.84 (m, 1H), 2.45-2.33 (m, 2H), 2.33-2.25 (m, 4H), 2.23 (s, 3H), 2.21-2.10 (m, 2H) ppm. 753 413 0.61 1H NMR (400 MHz, DMSO-D6) δ 9.76 (s, 1H), 9.24 (s, 1H), 9.04 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.59 (dd, J = 2.5, 1.4 Hz, 1H), 6.99 (t, J = 1.8 Hz, 1H), 6.81 (t, J = 1.9 Hz, 1H), 6.00 (t, J = 1.9 Hz, 1H), 3.93 (t, J = 7.2 Hz, 2H), 3.74-3.50 (m, 6H), 3.31-3.19 (m, 1H partially obscured by water peak), 2.36 (s, 4H). 754 493.18 0.64 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.62 (dt, J = 9.1, 2.2 Hz, 1H), 7.31 (dt, J = 8.0, 1.9 Hz, 1H), 6.89 (t, J = 2.0 Hz, 1H), 6.81 (s, 1H), 6.70 (t, J = 2.0 Hz, 1H), 6.18 (t, J = 2.2 Hz, 1H), 4.73 (q, J = 5.3, 4.4 Hz, 4H), 3.86 (s, 3H), 3.64 (d, J = 26.2 Hz, 1H), 3.33 (t, J = 4.9 Hz, 4H), 2.55 (s, 4H) ppm. 755 387.26 0.58 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.45-7.29 (m, 2H), 7.14 (s, 1H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 6.19 (s, 1H), 3.99-3.87 (m, 1H), 3.77-3.67 (m, 1H), 3.63-3.37 (m, 3H), 2.34 (s, 3H), 1.97-1.80 (m, 2H), 1.79-1.64 (m, 2H) ppm. 756 478.26 0.61 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 29.4 Hz, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.64 (t, J = 8.1 Hz, 1H), 7.57-7.47 (m, 2H), 7.39 (s, 1H), 6.70 (ddd, J = 107.8, 61.5, 35.6 Hz, 2H), 6.07 (d, J = 9.6 Hz, 1H), 4.16-4.07 (m, 2H), 3.91 (dt, J = 16.6, 8.3 Hz, 2H), 3.83-3.71 (m, 4H), 3.35 (ddd, J = 12.1, 6.8, 5.2 Hz, 1H), 2.47 (s, 4H) ppm. 757 477.25 0.65 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.62 (dt, J = 9.1, 2.2 Hz, 1H), 7.32 (dt, J = 8.2, 2.0 Hz, 1H), 7.26 (s, 1H), 6.79 (s, 1H), 6.73 (s, 1H), 6.44 (s, 1H), 4.75 (t, J = 6.4 Hz, 2H), 3.65 (d, J = 34.1 Hz, 1H), 3.35 (s, 4H), 2.56 (s, 4H), 2.36 (s, 3H) ppm. 758 460.26 0.58 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.62-7.47 (m, 2H), 7.42 (dd, J = 8.8, 2.4 Hz, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 5.81 (s, 1H), 4.71 (dt, J = 11.6, 6.3 Hz, 4H), 3.91 (s, 3H), 3.62-3.48 (m, 5H), 2.45 (t, J = 5.1 Hz, 4H) ppm. 759 416.42 0.58 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 8.03 (d, J = 1.1 Hz, 1H), 7.96-7.83 (m, 1H), 7.64 (dd, J = 7.3, 5.9 Hz, 2H), 7.13 (s, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 6.44 (s, 1H), 4.80-4.62 (m, 4H), 3.68-3.51 (m, 1H), 3.39-3.26 (m, 4H), 2.62-2.48 (m, 4H), 2.36 (s, 3H) ppm. 760 482.45 0.66 1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 7.01 (d, J = 1.5 Hz, 1H), 6.86 (tt, J = 8.6, 2.2 Hz, 1H), 4.86-4.58 (m, 4H), 3.81-3.63 (m, 3H), 3.56 (dt, J = 12.8, 6.4 Hz, 1H), 2.61-2.36 (m, 4H) ppm. 761 437.39 0.62 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.44-7.25 (m, 3H), 7.17 (d, J = 2.2 Hz, 1H), 6.82 (d, J = 2.1 Hz, 2H), 6.44 (d, J = 1.9 Hz, 1H), 4.79-4.66 (m, 4H), 3.59 (p, J = 6.5 Hz, 1H), 3.36-3.26 (m, 4H), 2.64 (q, J = 7.6 Hz, 2H), 2.57-2.48 (m, 4H), 2.33 (d, J = 1.9 Hz, 3H), 1.27 (t, J = 7.6 Hz, 4H) ppm. 762 430.33 0.59 1H NMR (300 MHz, DMSO-D6) δ 9.38 (s, 1H), 9.25 (s, 1H), 8.03 (q, J = 8.5 Hz, 4H), 7.17 (s, 1H), 6.94 (s, 1H), 6.36 (s, 1H), 4.54 (dt, J = 25.6, 6.3 Hz, 4H), 3.46 (q, J = 6.2 Hz, 1H), 3.16 (t, J = 4.7 Hz, 6H), 2.42 (t, J = 4.7 Hz, 6H), 1.18 (t, J = 7.5 Hz, 3H) ppm. 763 347.62 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.86 (s, 1H), 9.22 (s, 1H), 9.11 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 4.7, 1.3 Hz, 1H), 8.22 (ddd, J = 8.3, 2.6, 1.4 Hz, 1H), 7.63 (dd, J = 8.3, 4.7 Hz, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 6.93 (s, 1H), 3.82-3.69 (m, 4H), 3.24-3.11 (m, 4H) ppm. 764 401.21 0.63 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.52 (d, J = 20.1 Hz, 1H), 7.33-7.26 (m, 2H), 7.16 (s, 1H), 6.86-6.71 (m, 1H), 6.15 (s, 1H), 4.26 (dd, J = 12.6, 3.9 Hz, 1H), 3.96-3.80 (m, 1H), 3.45 (s, 3H), 3.39-3.27 (m, 1H), 3.02 (ddd, J = 19.2, 11.3, 5.9 Hz, 2H), 2.34 (s, 3H), 2.20-1.97 (m, 1H), 1.91-1.77 (m, 1H), 1.64-1.43 (m, 2H) ppm. 765 390.01 0.91 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H), 7.41 (s, 2H), 7.30 (d, J = 2.2 Hz, 1H), 6.86 (s, 1H), 6.22 (d, J = 7.2 Hz, 1H), 4.14 (s, 1H), 4.01 (ddd, J = 9.0, 6.4, 3.3 Hz, 2H), 3.90 (td, J = 8.5, 5.4 Hz, 2H), 2.55-2.16 (m, 4H), 1.93 (dd, J = 8.7, 5.2 Hz, 1H) ppm. 766 415.37 0.86 1H NMR (300 MHz, DMSO-D6) δ 9.19 (s, 1H), 8.98 (s, 1H), 6.81 (m, 4H), 6.44-6.26 (m, 2H), 5.84 (s, 1H), 5.58 (m, 0.5H), 5.38 (m, 0.5H), 4.13 (ddd, J = 20.0, 9.2, 5.8 Hz, 2H), 3.84 (ddd, J = 12.1, 9.1, 2.5 Hz, 2H), 3.51 (t, J = 5.5 Hz, 2H), 3.29 (s, 3H), 3.28-3.23 (m, 2H), 2.20 (s, 3H) ppm. 767 439.33 0.62 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.2, 2.2 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.20 (s, 1H), 6.75 (s, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 4.79-4.58 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.37-3.24 (m, 4H), 2.60-2.48 (m, 4H), 2.44 (s, 3H), 2.34 (s, 3H) ppm. 768 442.3 0.53 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.92-7.75 (m, 2H), 7.66-7.57 (m, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.25 (s, 2H), 6.92-6.59 (m, 1H), 5.80 (s, 1H), 4.08 (dd, J = 17.9, 10.3 Hz, 2H), 3.87 (dd, J = 8.1, 5.4 Hz, 2H), 3.76 (dd, J = 12.3, 7.7 Hz, 4H), 3.38-3.25 (m, 1H), 2.47 (s, 4H), 2.33 (s, 3H) ppm. 769 333.58 1.02 1H NMR (300 MHz, DMSO-D6) δ 9.49 (s, 1H), 9.12 (s, 1H), 7.82-7.67 (m, 2H), 7.61 (dt, J = 14.8, 7.3 Hz, 1H), 7.41 (s, 2H), 7.28-7.08 (m, 1H), 6.69 (s, 1H), 2.25 (s, 3H), 1.53 (ddd, J = 13.2, 8.3, 5.0 Hz, 1H), 0.90-0.79 (m, 2H), 0.79-0.55 (m, 2H) ppm. 770 427.59 0.98 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.64 (s, 1H), 7.57 (ddd, J = 10.7, 6.8, 2.6 Hz, 1H), 7.48-7.40 (m, 1H), 7.38 (s, 1H), 7.36-7.29 (m, 1H), 6.43 (s, 1H), 3.90-3.78 (m, 4H), 3.63-3.51 (m, 4H) ppm. 771 412.97 2.72 1H NMR (300 MHz, DMSO-D6) δ 10.45 (s, 1H), 9.46 (s, 1H), 9.19 (s, 1H), 7.70-7.57 (m, 2H), 7.37-7.31 (m, 1H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 6.83 (s, 1H), 6.39 (s, 1H), 3.64 (dd, J = 20.3, 13.0 Hz, 2H), 3.35 (s, 2H), 3.17-3.01 (m, 1H), 2.97 (d, J = 13.1 Hz, 1H), 2.73 (d, J = 4.8 Hz, 3H), 2.24 (s, 3H), 1.43 (s, 3H), 1.39 (s, 3H) ppm. 772 467.94 2.27 773 439.41 0.77 1H NMR (300 MHz, DMSO-D6) δ 9.31 (s, 1H), 9.14 (s, 1H), 7.64-7.54 (m, 2H), 7.22 (tt, J = 9.3, 2.2 Hz, 1H), 6.79 (s, 1H), 6.69 (s, 1H), 5.83 (s, 1H), 4.06-3.96 (m, 2H), 3.85 (t, J = 6.5 Hz, 2H), 3.72 (m, 1H), 3.33 (m, 4H), 2.20 (s, 3H), 1.93-1.73 (m, 4H) ppm. 774 370.21 0.84 1H NMR (400 MHz, DMSO-D6) δ 9.74 (s, 1H), 9.21 (s, 1H), 8.14 (s, 1H), 7.75-7.52 (m, 3H), 7.37-7.21 (m, 1H), 6.88 (s, 1H), 6.78 (s, 1H), 4.27 (d, J = 2.6 Hz, 2H), 3.82 (t, J = 5.4 Hz, 2H), 3.33 (s, 2H), 2.34 (s, 3H) ppm. 775 363.19 0.76 1H NMR (300 MHz, DMSO-D6) δ 9.93 (s, 1H), 9.22 (s, 1H), 7.84 (s, 1H), 7.72-7.59 (m, 2H), 7.43 (dt, J = 11.6, 2.2 Hz, 1H), 7.27 (tt, J = 9.3, 2.2 Hz, 1H), 6.89 (dd, J = 10.1, 1.4 Hz, 1H), 6.48 (s, 1H), 4.79 (d, J = 6.6 Hz, 2H), 4.66 (d, J = 6.6 Hz, 2H) ppm. 776 424 0.62 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H), 7.48-7.36 (m, 1H), 7.26 (d, J = 4.0 Hz, 1H), 7.00 (s, 1H), 6.68 (s, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 4.65 (t, J = 6.5 Hz, 2H), 4.58 (t, J = 6.2 Hz, 2H), 3.74-3.55 (m, 5H), 2.68-2.57 (m, 2H), 2.47-2.38 (m, 2H), 2.32 (s, 3H), 2.11-1.98 (m, 2H) ppm. 777 449.49 0.77 1H NMR (400 MHz, CD3CN) δ 8.60 (s, 1H), 7.41 (dt, J = 7.2, 3.6 Hz, 2H), 7.35 (s, 1H), 6.98-6.90 (m, 1H), 6.69 (t, J = 55.9 Hz, 1H), 6.49 (s, 1H), 4.31 (q, J = 5.9 Hz, 4H), 3.83 (s, 2H), 3.49-3.34 (m, 2H), 1.26-1.12 (m, 4H) ppm. 778 373.23 0.84 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.58 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.45-7.38 (m, 1H), 7.36-7.28 (m, 1H), 7.13 (t, J = 2.3 Hz, 1H), 6.79 (d, J = 3.6 Hz, 2H), 6.34 (t, J = 1.6 Hz, 1H), 5.02-4.92 (m, 1H), 4.09-3.89 (m, 4H), 2.35 (s, 3H), 2.23 (tq, J = 8.4, 4.2, 3.8 Hz, 2H) ppm. 779 427.31 0.62 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.43-7.29 (m, 3H), 7.09 (s, 1H), 6.92 (dd, J = 10.7, 2.2 Hz, 1H), 6.85 (s, 1H), 6.26 (dt, J = 12.0, 2.2 Hz, 1H), 4.81-4.68 (m, 4H), 3.57 (p, J = 6.4 Hz, 1H), 3.35-3.23 (m, 4H), 2.58-2.42 (m, 4H), 2.34 (s, 3H) ppm. 780 423.35 0.61 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.51 (dd, J = 6.5, 2.7 Hz, 1H), 7.45 (dt, J = 7.2, 3.7 Hz, 1H), 7.18-7.07 (m, 2H), 6.81 (s, 1H), 6.72 (s, 1H), 6.41 (s, 1H), 4.71 (p, J = 6.3 Hz, 5H), 3.58 (p, J = 6.4 Hz, 1H), 3.37-3.23 (m, 4H), 2.59-2.45 (m, 4H), 2.37 (d, J = 2.0 Hz, 3H), 2.34 (s, 3H) ppm. 781 443.3 0.61 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.62-7.42 (m, 2H), 7.40-7.35 (m, 1H), 7.12-6.93 (m, 2H), 6.81 (s, 1H), 6.26 (d, J = 11.8 Hz, 1H), 4.72 (p, J = 6.4 Hz, 4H), 3.97 (s, 3H), 3.60 (p, J = 6.5 Hz, 1H), 3.30 (t, J = 4.9 Hz, 4H), 2.54 (t, J = 4.9 Hz, 4H) ppm. 782 457.3 2.88 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.18 (d, J = 8.9 Hz, 2H), 6.59-6.51 (m, 2H), 6.48 (s, 1H), 5.88 (m, 1H), 3.99-3.87 (m, 5H), 3.67 (dd, J = 5.7, 3.8 Hz, 6H), 3.27 (tt, J = 6.7, 5.4 Hz, 1H), 2.38 (t, J = 4.6 Hz, 4H), 2.23 (s, 3H), 1.19 (s, 1H) ppm. 783 414 0.61 1H NMR (400 MHz, Acetone-D6) δ 9.13 (s, 1H), 8.78 (s, 1H), 8.35 (s, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.11 (d, J = 12.2 Hz, 2H), 6.33 (d, J = 12.4 Hz, 1H), 4.61 (s, 4H), 4.55 (s, 4H), 3.50 (s, 1H), 3.29 (s, 4H), 2.82 (d, J = 12.9 Hz, 10H), 2.48 (s, 4H) ppm. 784 447 0.69 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.65-7.50 (m, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.34-7.22 (m, 1H), 6.93 (t, J = 1.8 Hz, 1H), 6.67 (s, 1H), 6.53 (t, J = 1.9 Hz, 1H), 6.08 (t, J = 1.8 Hz, 1H), 3.98 (t, J = 7.1 Hz, 2H), 3.75 (t, J = 4.7 Hz, 6H), 3.35 (dd, J = 11.6, 6.0 Hz, 1H), 2.45 (m, 4H) ppm. 785 412 0.65 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 7.87 (dd, J = 12.2, 4.9 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.41-7.17 (m, 2H), 7.04 (s, 1H), 6.96 (s, 1H), 6.52 (s, 1H), 6.08 (s, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.87-3.67 (m, 6H), 3.48-3.23 (m, 1H) ppm. 786 415.25 0.65 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.40 (s, 1H), 7.32-7.28 (m, 2H), 7.15 (s, 1H), 6.80 (tt, J = 8.7, 2.3 Hz, 1H), 6.17 (s, 1H), 5.05 (d, J = 38.9 Hz, 1H), 4.31-4.05 (m, 2H), 3.38 (s, 3H), 3.34-3.25 (m, 1H), 2.99-2.83 (m, 1H), 2.68 (dd, J = 12.8, 10.1 Hz, 1H), 2.34 (s, 3H), 1.98-1.57 (m, 4H), 1.35-1.20 (m, 1H) ppm. 787 496.58 0.69 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 7.25 (dd, J = 7.6, 5.4 Hz, 2H), 6.83 (tt, J = 8.7, 2.2 Hz, 1H), 6.44 (s, 1H), 4.05-3.91 (m, 2H), 3.78 (ddd, J = 15.3, 12.2, 7.4 Hz, 2H), 3.62 (t, J = 5.1 Hz, 4H), 3.11-2.96 (m, 1H), 2.66 (dt, J = 10.5, 5.1 Hz, 2H), 2.60-2.46 (m, 2H), 2.18-2.06 (m, 1H), 1.93 (ddd, J = 15.6, 12.2, 8.1 Hz, 1H) ppm. 788 439.41 0.66 1H NMR (300 MHz, DMSO-D6) δ 9.27 (s, 1H), 9.14 (s, 1H), 7.65-7.53 (m, 2H), 7.22 (tt, J = 9.3, 2.3 Hz, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 5.80 (s, 1H), 4.37 (s, 1H), 3.91 (m, 2H), 3.79-3.67 (m, 2H), 3.53 (m, 4H), 2.80-2.68 (m, 1H), 2.58-2.52 (m, 1H), 1.73 (d, J = 8.3 Hz, 1H), 1.58 (d, J = 9.3 Hz, 1H) ppm. 789 471.27 0.61 1H NMR (300 MHz, MeOD + CDCl3) δ 8.69 (s, 1H), 7.78 (ddd, J = 11.1, 6.9, 2.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.37 (dd, J = 18.3, 8.8 Hz, 1H), 6.65 (d, J = 0.9 Hz, 1H), 4.80-4.69 (m, 4H), 3.76-3.64 (m, 4H), 3.63-3.51 (m, 1H), 2.96 (s, 3H), 2.56-2.39 (m, 4H) ppm. 790 445.04 0.68 791 401.36 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.32 (s, 1H), 9.16 (s, 1H), 7.66-7.55 (m, 2H), 7.24 (tt, J = 9.3, 2.3 Hz, 1H), 6.75 (s, 1H), 6.68 (s, 1H), 5.81 (s, 1H), 4.51 (s, 1H), 4.00 (t, J = 6.9 Hz, 2H), 3.74-3.62 (m, 1H), 3.48-3.39 (m, 4H), 2.59 (t, J = 5.9 Hz, 2H), 2.19 (s, 3H) ppm. 792 441.39 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.13 (s, 1H), 9.04 (s, 1H), 7.97 (ddd, J = 11.9, 7.1, 2.5 Hz, 1H), 7.77-7.58 (m, 2H), 6.82-6.77 (m, 1H), 6.52 (s, 1H), 5.84 (s, 1H), 5.79 (d, J = 5.2 Hz, 1H), 3.84-3.67 (m, 1H), 3.58 (t, J = 4.6 Hz, 4H), 2.90-2.79 (m, 1H), 2.32-2.16 (m, 6H), 2.14 (s, 3H), 2.02-1.89 (m, 2H) ppm. 793 420.2 0.65 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.56-7.41 (m, 3H), 7.35 (d, J = 1.6 Hz, 2H), 7.15-7.04 (m, 1H), 6.87 (s, 1H), 6.82-6.76 (m, 1H), 4.71 (dt, J = 12.4, 6.4 Hz, 4H), 3.65-3.53 (m, 1H), 3.40-3.24 (m, 4H), 2.63-2.41 (m, 4H) ppm. 794 445.32 0.6 1H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 7.90 (s, 1H), 7.80 (dd, J = 8.4, 2.1 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.07-6.96 (m, 2H), 6.95-6.50 (m, 2H), 6.27 (dt, J = 12.0, 2.2 Hz, 1H), 4.82-4.57 (m, 4H), 3.58 (p, J = 6.4 Hz, 1H), 3.31 (dd, J = 6.3, 3.8 Hz, 4H), 2.52 (dd, J = 6.1, 3.9 Hz, 4H) ppm. 795 483.25 0.75 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 6.7 Hz, 1H), 7.96 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.71-7.60 (m, 2H), 7.45 (s, 1H), 7.34 (s, 1H), 6.59 (t, J = 56.2 Hz, 1H), 6.40 (s, 1H), 4.38 (d, J = 13.1 Hz, 2H), 3.38 (s, 3H), 3.28 (d, J = 6.2 Hz, 2H), 2.88 (td, J = 12.9, 2.4 Hz, 2H), 1.96-1.77 (m, 3H), 1.38-1.18 (m, 2H) ppm. 796 1H NMR (400 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.19 (s, 1H), 7.71-7.60 (m, 3H), 7.32-7.18 (m, 2H), 6.73 (s, 1H), 3.69 (d, J = 8.8 Hz, 1H), 3.60 (d, J = 8.8 Hz, 1H), 2.77 (s, 3H), 2.31 (s, 3H), 1.68 (s, 3H) ppm. 797 441.44 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.26-9.18 (m, 1H), 9.17-9.10 (m, 1H), 7.73-7.56 (m, 2H), 7.25 (tt, J = 9.3, 2.3 Hz, 1H), 6.50-6.40 (m, 1H), 5.93-5.71 (m, 2H), 3.83-3.66 (m, 1H), 3.66-3.45 (m, 4H), 2.93-2.79 (m, 1H), 2.62-2.54 (m, 1H), 2.36-2.17 (m, 5H), 2.14 (s, 3H), 2.02-1.93 (m, 1H), 1.71-1.55 (m, 1H) ppm. 798 351.58 1.05 1H NMR (300 MHz, DMSO-D6) δ 9.55 (s, 1H), 9.17 (s, 1H), 7.74-7.51 (m, 2H), 7.41 (s, 2H), 7.25 (td, J = 9.3, 2.2 Hz, 1H), 6.70 (s, 1H), 2.26 (s, 3H), 1.53 (tt, J = 8.2, 5.0 Hz, 1H), 1.00-0.80 (m, 2H), 0.80-0.56 (m, 2H) ppm. 799 441.44 0.64 1H NMR (300 MHz, DMSO-D6) δ 9.17-9.09 (m, 1H), 9.09-9.00 (m, 1H), 8.03-7.90 (m, 1H), 7.77-7.58 (m, 2H), 6.80 (s, 1H), 6.56-6.45 (m, 1H), 5.91-5.67 (m, 2H), 3.89-3.67 (m, 1H), 3.64-3.48 (m, 4H), 2.91-2.79 (m, 1H), 2.31-2.18 (m, 5H), 2.14 (s, 3H), 2.00-1.91 (m, 1H), 1.70-1.57 (m, 1H) ppm. 800 441.12 0.68 1H NMR (300 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.59 (dd, J = 8.6, 2.1 Hz, 2H), 7.23 (tt, J = 9.2, 4.6 Hz, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 5.84 (s, 1H), 3.95 (d, J = 30.9 Hz, 2H), 3.66 (m, 1H), 3.53 (m, 5H), 3.21-3.10 (m, 1H), 2.64 (d, J = 12.0 Hz, 1H), 2.41 (m, 1H), 2.23-2.08 (m, 4H), 0.91 (d, J = 6.4 Hz, 3H) ppm. 801 427.29 0.74 1H NMR (400 MHz, DMSO-D6) δ 9.66 (s, 1H), 9.20 (s, 1H), 7.66 (dd, J = 8.5, 2.2 Hz, 2H), 7.58 (s, 1H), 7.27 (ddd, J = 9.3, 5.8, 2.3 Hz, 1H), 6.65 (s, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.2 Hz, 2H), 3.43-3.27 (m, 2H), 2.79 (app d, J = 10.9 Hz, 2H), 2.48-2.44 (m, 1H), 2.32 (s, 3H), 1.89-1.72 (m, 6H) ppm. 802 437.21 0.67 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.52-7.41 (m, 3H), 7.14 (t, J = 2.0 Hz, 1H), 7.10-7.00 (m, 1H), 6.85 (s, 1H), 6.66 (s, 1H), 6.46 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.39-3.19 (m, 4H), 2.70-2.52 (m, 6H), 1.44 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H) ppm. 803 431 0.67 1H NMR (400 MHz, Acetone-D6) δ 8.85 (s, 1H), 8.61 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.54 (q, J = 9.4 Hz, 1H), 7.11 (s, 2H), 6.29 (d, J = 12.4 Hz, 1H), 4.61 (s, 2H), 4.54 (s, 2H), 3.49 (s, 1H), 3.27 (s, 4H), 2.83 (d, J = 12.9 Hz, 3H), 2.47 (s, 4H) ppm. 804 463.41 0.67 1H NMR (300 MHz, DMSO-D6) δ 9.63 (s, 1H), 9.18 (s, 1H), 7.69-7.54 (m, 2H), 7.24 (tt, J = 9.3, 2.2 Hz, 1H), 7.16-6.67 (m, 3H), 6.14 (s, 1H), 3.95 (t, J = 7.1 Hz, 2H), 3.69-3.54 (m, 6H), 2.36 (m, 4H) ppm. 805 428.28 0.8 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.28-7.25 (m, 2H), 7.23 (t, J = 2.3 Hz, 1H), 6.86-6.74 (m, 4H), 6.42 (t, J = 1.7 Hz, 1H), 4.60 (tt, J = 6.9, 3.5 Hz, 1H), 3.87 (ddd, J = 12.5, 8.1, 3.8 Hz, 1H), 3.76 (ddd, J = 13.6, 8.1, 3.6 Hz, 1H), 3.63 (ddd, J = 13.4, 7.3, 4.0 Hz, 1H), 3.43 (ddd, J = 13.6, 7.4, 3.8 Hz, 1H), 2.36 (s, 3H), 2.15 (s, 3H), 2.07-1.80 (m, 4H) ppm. 806 446.21 0.66 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.61-7.40 (m, 4H), 7.34 (s, 1H), 7.15-7.03 (m, 1H), 6.61 (t, J = 56.1 Hz, 1H), 6.39 (s, 1H), 4.82-4.62 (m, 4H), 3.72-3.61 (m, 4H), 3.56 (dt, J = 12.8, 6.5 Hz, 1H), 2.53-2.38 (m, 4H) ppm. 807 483.25 0.89 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.86-7.82 (m, 2H), 7.64 (t, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 15.9 Hz, 1H), 6.75 (t, J = 56.2 Hz, 1H), 6.46 (s, 1H), 4.38 (d, J = 13.1 Hz, 2H), 3.38 (s, 3H), 3.26 (t, J = 18.4 Hz, 2H), 2.89 (td, J = 12.9, 2.4 Hz, 2H), 1.95-1.75 (m, 3H), 1.29 (tt, J = 12.9, 6.3 Hz, 2H) ppm. 808 441 0.68 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.34-7.14 (m, 3H), 6.77 (tt, J = 8.7, 2.3 Hz, 1H), 6.69-6.56 (m, 3H), 5.96 (s, 1H), 4.02 (t, J = 6.9 Hz, 2H), 3.82 (t, J = 6.2 Hz, 2H), 3.79-3.71 (m, 2H), 3.71-3.62 (m, 2H), 3.62-3.48 (m, 1H), 2.63 (dd, J = 7.9, 3.7 Hz, 3H), 2.30 (s, 3H), 1.98-1.82 (m, 2H) ppm. 809 442.43 0.61 810 404.01 0.84 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 2.2 Hz, 2H), 6.90-6.78 (m, 2H), 6.60-6.50 (m, 1H), 4.09 (d, J = 11.6 Hz, 2H), 3.68-3.22 (m, 3H), 2.39 (s, 3H), 1.77 (qd, J = 11.7, 4.2 Hz, 2H) ppm. 811 450 0.66 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.41 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 7.91-7.79 (m, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.22 (ddd, J = 7.3, 4.9, 1.1 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.56 (s, 1H), 5.77 (d, J = 2.0 Hz, 1H), 4.46 (dt, J = 12.1, 6.1 Hz, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.85-3.69 (m, 6H), 3.38 (dt, J = 11.2, 5.6 Hz, 1H), 2.56-2.43 (m, 4H), 2.12 (s, 3H), 1.33 (d, J = 6.1 Hz, 6H) ppm. 812 416.21 0.62 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.27-7.20 (m, 1H), 7.15 (t, J = 2.2 Hz, 1H), 6.86-6.76 (m, 2H), 6.67 (s, 1H), 6.41 (t, J = 1.6 Hz, 1H), 4.21 (s, 2H), 3.78 (s, 4H), 2.88 (s, 2H), 2.65 (s, 4H), 2.36 (s, 3H). 813 414.38 0.82 1H NMR (300 MHz, DMSO-D6) δ 9.44 (s, 1H), 9.15 (s, 1H), 8.23 (d, J = 7.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.2 Hz, 2H), 7.30-7.19 (m, 1H), 7.02 (s, 1H), 6.95 (s, 1H), 6.17 (s, 1H), 4.85-4.74 (m, 1H), 4.32-4.21 (m, 1H), 2.37 (t, J = 6.3 Hz, 4H), 2.24 (s, 3H), 1.80 (s, 3H) ppm. 814 425.9 2.63 815 401.26 0.6 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.31-7.29 (m, 2H), 7.25 (s, 1H), 7.02 (s, 1H), 6.81 (tt, J = 8.7, 2.3 Hz, 1H), 6.15 (s, 1H), 3.87 (dd, J = 13.2, 3.4 Hz, 1H), 3.79 (ddd, J = 13.0, 6.6, 3.8 Hz, 1H), 3.55 (t, J = 9.2 Hz, 2H), 3.46 (dd, J = 13.2, 7.2 Hz, 1H), 3.34-3.19 (m, 1H), 2.33 (s, 3H), 1.89 (dtd, J = 16.4, 7.5, 3.8 Hz, 2H), 1.73 (dtd, J = 10.6, 7.3, 3.8 Hz, 1H), 1.61-1.50 (m, 1H), 1.39 (ddd, J = 16.5, 8.2, 3.9 Hz, 1H) ppm. 816 415.37 0.68 1H NMR (300 MHz, DMSO-D6) δ 9.33 (s, 1H), 9.16 (s, 1H), 7.66-7.54 (m, 2H), 7.22 (tt, J = 9.3, 2.3 Hz, 1H), 6.78 (s, 1H), 6.67 (s, 1H), 5.80 (s, 1H), 4.00 (t, J = 6.9 Hz, 2H), 3.73-3.61 (m, 1H), 3.47-3.39 (m, 2H), 3.36 (t, J = 5.7 Hz, 2H), 3.25 (s, 3H), 2.67 (t, J = 5.7 Hz, 2H), 2.20 (s, 3H) ppm. 817 441.39 0.82 1H NMR (300 MHz, DMSO-D6) δ 9.31 (s, 1H), 9.15 (s, 1H), 7.58 (m, 2H), 7.22 (tt, J = 9.3, 2.2 Hz, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 5.84 (s, 1H), 4.03 (m, 2H), 3.87-3.75 (m, 3H), 3.27 (m, 4H), 2.20 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H) ppm. 818 407 0.58 1H NMR (400 MHz, CDCl3) δ 9.14 (d, J = 1.4 Hz, 1H), 8.90 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 8.38 (dd, J = 2.5, 1.5 Hz, 1H), 7.05 (s, 1H), 6.79 (s, 1H), 6.52 (s, 1H), 6.18 (s, 1H), 4.66 (t, J = 6.5 Hz, 2H), 4.58 (t, J = 6.2 Hz, 2H), 3.75-3.55 (m, 5H), 2.68-2.53 (m, 2H), 2.47-2.36 (m, 2H), 2.32 (s, 3H), 2.11-2.00 (m, 2H) ppm. 819 430 0.63 1H NMR (400 MHz, DMSO-D6) δ 9.70 (s, 1H), 9.35 (s, 1H), 8.35 (d, J = 5.6 Hz, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.57 (s, 1H), 7.01 (s, 1H), 6.82 (s, 1H), 6.00 (s, 1H), 3.97 (t, J = 7.0 Hz, 2H), 3.66 (dd, J = 15.0, 7.8 Hz, 6H), 3.30 (s, 4H), 2.39 (s, 4H) ppm. 820 441.29 0.63 1H NMR (400 MHz, DMSO-D6) δ 9.10 (s, 1H), 8.30 (s, 1H), 7.58-7.48 (m, 2H), 7.22 (tt, J = 9.3, 2.3 Hz, 1H), 6.99 (s, 1H), 6.10 (s, 1H), 3.93 (t, J = 7.0 Hz, 2H), 3.64-3.51 (m, 6H), 3.14 (dd, J = 12.5, 6.2 Hz, 1H), 2.33 (s, 4H), 2.21 (s, 3H), 1.98 (s, 3H) ppm. 821 368.18 0.61 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.32-7.28 (m, 2H), 7.22 (s, 1H), 6.82 (tt, J = 8.7, 2.3 Hz, 1H), 5.81 (s, 1H), 4.25 (ddd, J = 14.2, 12.2, 7.3 Hz, 4H), 3.59 (tt, J = 8.6, 6.4 Hz, 1H), 2.34 (d, J = 14.8 Hz, 3H) ppm. 822 384.25 0.87 1H NMR (300 MHz, DMSO-D6) δ 9.24 (s, 1H), 9.14 (s, 1H), 7.59 (dd, J = 8.6, 2.2 Hz, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.90-6.80 (m, 1H), 6.69 (s, 1H), 6.02 (s, 1H), 4.65-4.56 (m, 1H), 4.43 (s, 1H), 3.80-3.68 (m, 2H), 3.50 (dd, J = 9.1, 1.6 Hz, 1H), 2.98 (d, J = 9.2 Hz, 1H), 2.21 (s, 3H), 1.97-1.78 (m, 2H) ppm. 823 460.25 0.66 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.52-7.43 (m, 4H), 7.36 (s, 1H), 7.13-7.01 (m, 1H), 6.60 (t, J = 56.2 Hz, 1H), 6.38 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.75-3.50 (m, 4H), 2.57-2.37 (m, 4H), 1.40 (s, 3H) ppm. 824 457.38 0.76 1H NMR (300 MHz, DMSO-D6) δ 9.32 (s, 1H), 9.14 (s, 1H), 7.64-7.53 (m, 2H), 7.23 (m, 1H), 6.79 (m, 1H), 6.70 (s, 1H), 5.84 (s, 1H), 4.01 (m, 2H), 3.84 (m, 3H), 3.45 (m, 4H), 3.28 (s, 1.5H), 3.23 (s, 1.5H), 2.93 (s, 1.5H), 2.86 (s, 1.5H), 2.21 (s, 3H) ppm. 825 407 0.59 1H NMR (400 MHz, CDCl3) δ 9.17 (d, J = 1.4 Hz, 1H), 8.90 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 8.38 (dd, J = 2.5, 1.5 Hz, 1H), 6.75 (s, 1H), 6.70 (s, 1H), 6.64 (s, 1H), 5.96 (s, 1H), 4.03 (t, J = 6.9 Hz, 2H), 3.82 (t, J = 6.1 Hz, 2H), 3.79-3.73 (m, 2H), 3.73-3.65 (m, 2H), 3.62-3.53 (m, 1H), 2.64 (t, J = 5.7 Hz, 3H), 2.31 (s, 3H), 2.01-1.86 (m, 2H) ppm. 826 441.35 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.14 (s, 1H), 9.06 (s, 1H), 7.98 (ddd, J = 12.0, 7.0, 2.5 Hz, 1H), 7.79-7.57 (m, 2H), 6.98-6.88 (m, 1H), 6.51-6.43 (m, 1H), 5.89 (s, 1H), 5.71 (d, J = 6.9 Hz, 1H), 3.65-3.45 (m, 5H), 2.65-2.54 (m, 2H), 2.47-2.41 (m, 1H), 2.31-2.17 (m, 4H), 2.13 (s, 3H), 1.71-1.55 (m, 2H) ppm. 827 429 0.68 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.52-7.37 (m, 3H), 7.12-6.96 (m, 1H), 6.92 (t, J = 1.9 Hz, 1H), 6.68 (s, 1H), 6.59 (t, J = 2.0 Hz, 1H), 6.08 (t, J = 1.9 Hz, 1H), 3.99 (t, J = 7.1 Hz, 2H), 3.76 (dd, J = 7.7, 5.2 Hz, 6H), 3.41-3.27 (m, 1H), 2.45 (m, 4H) ppm. 828 346.09 0.76 1H NMR (300 MHz, MeOD + CDCl3) δ 8.37 (s, 1H), 7.58-7.43 (m, 4H), 7.40 (s, 1H), 7.14-7.00 (m, 1H), 6.37 (s, 1H), 4.85-4.56 (m, 4H), 3.63 (dd, J = 11.2, 6.2 Hz, 4H), 3.54 (dd, J = 12.8, 6.4 Hz, 1H), 2.58-2.31 (m, 4H), 1.96 (t, J = 18.3 Hz, 3H) ppm. 829 437.39 0.63 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.56-7.49 (m, 1H), 7.45 (dt, J = 7.4, 3.6 Hz, 1H), 7.18-7.07 (m, 2H), 6.84 (s, 1H), 6.81 (s, 1H), 6.44 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 3.58 (p, J = 6.4 Hz, 1H), 3.30 (t, J = 5.0 Hz, 4H), 2.63 (q, J = 7.6 Hz, 2H), 2.53 (t, J = 5.0 Hz, 4H), 2.37 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H) ppm. 830 471 0.7 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.30-7.18 (m, 3H), 6.77 (tt, J = 8.7, 2.2 Hz, 1H), 6.67 (s, 1H), 6.62 (t, J = 1.9 Hz, 1H), 6.25 (t, J = 1.9 Hz, 1H), 5.69 (t, J = 2.0 Hz, 1H), 4.56 (dt, J = 12.1, 6.1 Hz, 1H), 3.97 (t, J = 7.0 Hz, 2H), 3.84-3.67 (m, 6H), 3.40-3.24 (m, 1H), 2.45 (s, 4H), 1.37 (d, J = 6.1 Hz, 6H) ppm. 831 447.43 0.72 1H NMR (300 MHz, DMSO-D6) δ 9.38 (s, 1H), 9.17 (s, 1H), 7.61 (m, 2H), 7.33-7.18 (m, 2H), 6.79 (s, 1H), 6.34 (s, 1H), 3.77 (m, 1H), 3.64 (d, J = 12.0 Hz, 1H), 3.44 (m, 1H), 3.03 (d, J = 10.7 Hz, 1H), 2.79 (td, J = 11.9, 6.0 Hz, 1H), 2.67-2.52 (m, 3H), 2.38 (m, 2H), 2.23 (s, 3H), 2.11-1.89 (m, 1H) ppm. 832 397.22 0.82 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.29-7.25 (m, 2H), 7.10 (t, J = 2.2 Hz, 1H), 6.85-6.78 (m, 2H), 6.73 (s, 1H), 6.35 (t, J = 1.6 Hz, 1H), 6.29 (t, J = 2.1 Hz, 1H), 4.57 (t, J = 5.3 Hz, 2H), 4.39 (t, J = 5.3 Hz, 2H), 2.34 (s, 3H) ppm. 833 441.26 0.6 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.92 (s, 1H), 7.82-7.70 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 6.73 (dd, J = 62.6, 49.9 Hz, 3H), 6.42 (s, 1H), 4.79-4.65 (m, 4H), 3.69-3.51 (m, 1H), 3.46-3.23 (m, 4H), 2.53 (dd, J = 11.9, 7.0 Hz, 4H), 2.35 (s, 3H) ppm. 834 459.21 0.64 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.00 (dd, J = 7.8, 1.7 Hz, 1H), 7.60 (ddd, J = 10.7, 6.8, 2.6 Hz, 1H), 7.48-7.39 (m, 1H), 7.34 (dd, J = 9.3, 8.1 Hz, 1H), 6.95 (d, J = 3.9 Hz, 1H), 6.74 (d, J = 4.5 Hz, 1H), 4.75-4.55 (m, 4H), 3.62 (d, J = 1.4 Hz, 2H), 3.58-3.45 (m, 1H), 2.60 (s, 4H), 2.39 (s, 7H) ppm. 835 383.58 0.88 1H NMR (300 MHz, DMSO-D6) δ 9.82 (s, 1H), 9.20 (s, 1H), 7.74-7.57 (m, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.42 (s, 1H), 7.27 (tt, J = 9.3, 2.3 Hz, 1H), 6.92 (s, 1H), 3.83-3.68 (m, 4H), 3.23-3.11 (m, 4H) ppm. 836 423.4 0.61 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.40 (dd, J = 10.3, 1.7 Hz, 1H), 7.36-7.29 (m, 2H), 7.15 (s, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 6.41 (s, 1H), 4.77-4.63 (m, 4H), 3.59 (p, J = 6.4 Hz, 1H), 3.36-3.24 (m, 4H), 2.61-2.47 (m, 4H), 2.34 (s, 6H) ppm. 837 405.22 0.63 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 6.7 Hz, 1H), 7.98 (s, 1H), 7.93-7.83 (m, 1H), 7.76-7.55 (m, 2H), 7.27 (d, J = 3.1 Hz, 2H), 6.12 (s, 1H), 3.89-3.77 (m, 4H), 3.58-3.43 (m, 4H), 2.36 (s, 3H) ppm. 838 333 0.69 1H NMR (300 MHz, MeOD + CDCl3) δ 8.48 (s, 1H), 7.97-7.68 (m, 3H), 7.59-7.30 (m, 5H), 7.08-6.78 (m, 3H), 2.36 (s, 3H) ppm. 839 469.21 0.94 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.23 (s, 1H), 7.13-7.10 (m, 2H), 6.68 (ddd, J = 8.7, 5.5, 2.2 Hz, 1H), 6.32 (s, 1H), 4.22 (d, J = 13.0 Hz, 2H), 3.23 (s, 3H), 3.13 (d, J = 6.2 Hz, 2H), 2.74 (td, J = 13.0, 2.4 Hz, 2H), 1.73 (dd, J = 17.9, 7.9 Hz, 3H), 1.19-1.10 (m, 2H) ppm. 840 441.63 0.65 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.62 (ddd, J = 10.8, 6.8, 2.5 Hz, 1H), 7.47-7.37 (m, 1H), 7.33 (t, J = 8.7 Hz, 2H), 7.27 (s, 1H), 6.78 (s, 1H), 6.67 (s, 1H), 4.66 (p, J = 6.4 Hz, 4H), 3.61-3.43 (m, 3H), 2.49 (d, J = 62.8 Hz, 11H) ppm. 841 421.26 2.73 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.53-7.46 (m, 2H), 6.96-6.89 (m, 2H), 6.61-6.52 (m, 2H), 6.42 (s, 1H), 5.85 (s, 1H), 3.90 (t, J = 7.0 Hz, 2H), 3.79 (s, 3H), 3.67 (dd, J = 5.8, 3.6 Hz, 6H), 3.32-3.21 (m, 1H), 2.38 (t, J = 4.5 Hz, 4H), 2.24-2.19 (m, 3H) ppm. 842 403.24 0.55 1H NMR (300 MHz, DMSO-D6) δ 9.78 (s, 1H), 9.20 (s, 1H), 9.10 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 4.7, 1.4 Hz, 1H), 8.21 (ddd, J = 8.3, 2.6, 1.4 Hz, 1H), 7.62 (dd, J = 8.3, 4.7 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 6.91 (s, 1H), 4.53 (dt, J = 12.1, 6.3 Hz, 4H), 3.45 (dd, J = 12.6, 6.2 Hz, 1H), 3.28-3.14 (m, 4H), 2.46-2.30 (m, 4H) ppm. 843 399.28 0.6 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.31-7.25 (m, 4H), 7.23-7.09 (m, 2H), 6.88-6.73 (m, 1H), 5.87 (d, J = 22.2 Hz, 1H), 4.67 (t, J = 5.2 Hz, 1H), 4.00 (dd, J = 15.1, 7.8 Hz, 1H), 3.88 (td, J = 8.1, 4.9 Hz, 1H), 3.72 (d, J = 11.6 Hz, 1H), 3.66 (dd, J = 10.6, 8.7 Hz, 1H), 3.51 (dd, J = 11.8, 5.2 Hz, 1H), 3.37 (dd, J = 10.7, 5.4 Hz, 1H), 3.07-2.95 (m, 1H), 2.34 (s, 3H), 2.20 (tt, J = 15.5, 7.8 Hz, 1H), 1.91 (dt, J = 12.0, 7.9 Hz, 1H) ppm. 845 416.21 0.61 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.65-7.55 (m, 1H), 7.46-7.38 (m, 1H), 7.37-7.26 (m, 1H), 7.16-7.09 (m, 1H), 6.84 (d, J = 3.1 Hz, 2H), 6.40 (d, J = 2.3 Hz, 1H), 4.18 (t, J = 5.8 Hz, 2H), 3.82-3.71 (m, 4H), 2.85 (t, J = 5.8 Hz, 2H), 2.62 (t, J = 4.7 Hz, 4H), 2.35 (s, 3H) ppm. 846 366.16 0.69 1H NMR (300 MHz, DMSO-D6) δ 9.74 (s, 1H), 9.23 (s, 1H), 9.14 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.58 (dd, J = 2.5, 1.4 Hz, 1H), 7.72 (s, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 3.72 (d, J = 8.8 Hz, 1H), 3.61 (d, J = 8.8 Hz, 1H), 2.78 (s, 3H), 2.32 (s, 3H), 1.69 (s, 3H) ppm. 847 432.29 0.57 1H NMR (400 MHz, DMSO-D6) δ 9.95 (s, 1H), 9.22 (s, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.39 (s, 1H), 7.29 (t, J = 9.1 Hz, 1H), 6.14 (s, 1H), 4.57 (t, J = 6.3 Hz, 2H), 4.48 (t, J = 5.9 Hz, 2H), 3.50-3.37 (m, 5H), 2.39 (s, 4H) ppm. 848 442.3 0.55 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.87 (s, 1H), 7.82 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 6.91-6.59 (m, 1H), 6.13 (s, 1H), 4.76-4.67 (m, 4H), 3.64-3.50 (m, 5H), 2.47 (dd, J = 15.6, 10.6 Hz, 4H), 2.34 (d, J = 8.6 Hz, 3H) ppm. 849 478.66 0.68 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.58 (ddd, J = 10.7, 6.8, 2.6 Hz, 1H), 7.47 (s, 1H), 7.46-7.38 (m, 1H), 7.38-7.29 (m, 2H), 6.59 (t, J = 56.2 Hz, 1H), 6.38 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.71-3.56 (m, 4H), 2.55-2.40 (m, 4H), 1.40 (s, 3H) ppm. 850 442.94 2.72 1H NMR (300 MHz, DMSO-D6) δ 10.36 (s, 1H), 9.44 (s, 1H), 9.18 (s, 1H), 7.69-7.57 (m, 2H), 7.27 (tt, J = 9.2, 2.3 Hz, 1H), 7.13 (s, 1H), 6.97 (s, 1H), 6.39 (s, 1H), 3.75 (d, J = 10.9 Hz, 2H), 3.59 (d, J = 10.1 Hz, 2H), 3.41 (t, J = 5.9 Hz, 2H), 3.26 (s, 3H), 3.23-2.99 (m, 6H), 2.25 (s, 3H), 2.06-1.90 (m, 2H) ppm. 851 426.1 0.69 852 401.41 0.79 1H NMR (300 MHz, DMSO-D6) δ 9.19 (s, 1H), 8.97 (s, 1H), 6.94-6.61 (m, 4H), 6.45-6.21 (m, 2H), 5.83 (s, 1H), 5.58 (m, 0.5H), 5.39 (m, 0.5H), 4.73 (t, J = 5.4 Hz, 1H), 4.22-4.01 (m, 2H), 3.91-3.74 (m, 2H), 3.58 (q, J = 5.8 Hz, 2H), 3.21-3.11 (m, 2H), 2.20 (s, 3H) ppm. 853 439.37 0.66 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 7.53 (s, 1H), 7.47-7.31 (m, 2H), 6.86 (s, 1H), 6.50 (s, 1H), 4.72 (dt, J = 18.6, 6.3 Hz, 4H), 3.64 (t, J = 16.6 Hz, 5H), 2.48 (d, J = 4.8 Hz, 4H) ppm. 854 487.3 0.61 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.92-7.75 (m, 1H), 7.75-7.52 (m, 2H), 7.30 (t, J = 1.9 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H), 6.44 (s, 1H), 3.84 (d, J = 12.6 Hz, 2H), 3.80-3.72 (m, 4H), 2.80 (td, J = 12.3, 2.2 Hz, 2H), 2.66-2.59 (m, 4H), 2.38 (ddd, J = 14.0, 7.0, 3.2 Hz, 1H), 2.34 (s, 3H), 1.98 (s, 1H), 1.69 (dq, J = 12.2, 8.2 Hz, 2H) ppm. 855 429 0.7 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.43-7.18 (m, 4H), 7.12 (s, 1H), 6.78 (tt, J = 8.7, 2.2 Hz, 1H), 6.13 (s, 1H), 4.28 (d, J = 12.9 Hz, 2H), 3.45 (t, J = 6.5 Hz, 2H), 3.35 (s, 3H), 2.77 (td, J = 12.7, 2.2 Hz, 2H), 2.32 (s, 3H), 1.77 (d, J = 12.4 Hz, 2H), 1.63 (dd, J = 10.2, 7.3 Hz, 2H), 1.55 (dd, J = 13.1, 6.5 Hz, 2H), 1.34-1.19 (m, 3H) ppm. 856 390.96 0.92 857 455.4 0.7 1H NMR (300 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.66-7.51 (m, 2H), 7.23 (tt, J = 9.3, 2.3 Hz, 1H), 6.75 (s, 1H), 6.68 (s, 1H), 5.81 (s, 1H), 3.89 (t, J = 7.0 Hz, 2H), 3.56 (m, 4H), 3.28-3.18 (m, 1H), 2.71 (d, J = 10.3 Hz, 2H), 2.19 (s, 3H), 1.58 (t, J = 10.6 Hz, 2H), 1.06 (d, J = 6.2 Hz, 5H) ppm. 858 415.37 0.67 1H NMR (300 MHz, DMSO-D6) δ 9.35 (s, 1H), 9.17 (s, 1H), 7.76-7.63 (m, 2H), 7.24 (tt, J = 9.3, 2.3 Hz, 1H), 7.08 (s, 1H), 6.67 (s, 2H), 6.14 (s, 1H), 3.90 (s, 4H), 3.51 (t, J = 6.4 Hz, 2H), 3.45-3.19 (m, 6H), 2.20 (s, 3H). 859 480.24 0.64 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.77 (dd, J = 6.2, 2.6 Hz, 1H), 7.64-7.51 (m, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.31 (t, J = 7.5 Hz, 1H), 6.60 (t, J = 56.1 Hz, 1H), 6.38 (s, 1H), 4.71 (p, J = 6.3 Hz, 4H), 3.64 (t, J = 5.1 Hz, 4H), 3.55 (p, J = 6.4 Hz, 1H), 2.45 (t, J = 5.1 Hz, 4H) ppm. 860 460.07 0.67 1H NMR (300 MHz, MeOD + CDCl3) δ 8.37 (s, 1H), 7.58-7.43 (m, 4H), 7.40 (s, 1H), 7.14-7.00 (m, 1H), 6.37 (s, 1H), 4.85-4.56 (m, 4H), 3.63 (dd, J = 11.2, 6.2 Hz, 4H), 3.54 (dd, J = 12.8, 6.4 Hz, 1H), 2.58-2.31 (m, 4H), 1.96 (t, J = 18.3 Hz, 3H) ppm. 861 441.39 0.65 1H NMR (300 MHz, DMSO-D6) δ 9.22 (s, 1H), 9.15 (s, 1H), 7.69-7.61 (m, 2H), 7.24 (tt, J = 9.3, 2.4 Hz, 1H), 7.01 (s, 1H), 6.42 (s, 1H), 5.90 (s, 1H), 5.75 (d, J = 6.8 Hz, 1H), 3.65-3.45 (m, 5H), 2.63-2.54 (m, 2H), 2.48-2.41 (m, 1H), 2.31-2.18 (m, 4H), 2.13 (s, 3H), 1.65 (t, J = 9.4 Hz, 2H) ppm. 862 450 0.66 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.42 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.85 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.80-7.68 (m, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.31-7.16 (m, 2H), 6.58 (s, 1H), 6.24 (d, J = 2.2 Hz, 1H), 4.79-4.64 (m, 4H), 4.47 (dt, J = 12.1, 6.1 Hz, 1H), 3.67-3.51 (m, 1H), 3.39-3.19 (m, 4H), 2.61-2.45 (m, 4H), 2.14 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H) ppm. 863 413 0.59 864 455.67 0.64 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.48 (s, 1H), 7.30 (d, J = 5.1 Hz, 1H), 7.27-7.17 (m, 2H), 6.91-6.71 (m, 3H), 4.65 (dt, J = 12.4, 6.4 Hz, 4H), 3.84 (s, 2H), 3.53 (dt, J = 12.7, 6.3 Hz, 3H), 2.41 (s, 7H) ppm. 865 387.14 0.86 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.45 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.31-7.22 (m, 1H), 7.20-7.13 (m, 1H), 6.97 (t, J = 2.2 Hz, 1H), 6.68 (d, J = 1.6 Hz, 1H), 6.24 (t, J = 1.6 Hz, 1H), 3.88-3.73 (m, 4H), 3.72-3.63 (m, 1H), 3.59 (dd, J = 8.8, 5.3 Hz, 1H), 2.64 (tq, J = 13.5, 6.7, 6.2 Hz, 1H), 2.20 (s, 3H), 2.00 (dtd, J = 13.5, 8.2, 5.6 Hz, 1H), 1.70-1.56 (m, 1H) ppm. 866 441.35 0.67 1H NMR (300 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.70-7.52 (m, 2H), 7.31-7.15 (m, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 5.77 (s, 1H), 3.91 (t, J = 7.3 Hz, 2H), 3.62-3.51 (m, 4H), 3.44 (t, J = 6.3 Hz, 2H), 3.00-2.81 (m, 1H), 2.56 (d, J = 7.4 Hz, 2H), 2.37 (s, 4H), 2.18 (s, 3H) ppm. 867 441.22 0.8 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.97 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.75-7.60 (m, 2H), 7.55 (s, 1H), 7.37 (s, 1H), 6.61 (t, J = 56.1 Hz, 1H), 6.38 (s, 1H), 3.92-3.81 (m, 4H), 3.61-3.49 (m, 4H) ppm. 868 553.43 0.52 1H NMR (300 MHz, DMSO-D6) δ 9.17 (s, 1H), 9.12 (s, 1H), 7.60-7.56 (m, 2H), 7.25-7.17 (m, 1H), 6.21 (d, J = 1.7 Hz, 2H), 5.09 (s, 1H), 3.86 (t, J = 6.9 Hz, 4H), 3.65-3.50 (m, 12H), 3.26-3.17 (m, 2H), 2.34 (s, 8H) ppm. 869 390.01 0.9 1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.50-7.35 (m, 2H), 7.32-7.29 (m, 1H), 7.27 (d, J = 1.9 Hz, 1H), 6.85 (tt, J = 8.7, 2.3 Hz, 1H), 6.02-5.73 (m, 1H), 4.89 (d, J = 6.0 Hz, 2H), 4.61 (d, J = 6.0 Hz, 2H), 2.35 (d, J = 1.0 Hz, 2H), 1.73 (s, 3H) ppm.

TABLE 3B Analytical Data LC/MS Cmpd Ret. No. in LCMS Time US (M + H) (min) ¹H-NMR 870 445.09 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.89 (s, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.16 (s, 1H), 5.89 (s, 1H), 3.90 (t, J = 6.8 Hz, 2H), 3.59 (d, J = 5.8 Hz, 5H), 2.34 (s, 4H), 2.17 (d, J = 2.2 Hz, 3H) ppm. 871 455.22 0.7 872 442.94 2.73 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.16 (s, 1H), 7.69-7.62 (m, 2H), 7.30-7.20 (m, 1H), 6.97 (s, 1H), 6.63 (s, 1H), 6.04 (s, 1H), 3.94 (t, J = 15.1 Hz, 2H), 3.83-3.78 (m, 1H), 3.47-3.40 (m, 4H), 3.36-3.23 (m, 3H), 2.20 (s, 3H), 1.84-1.79 (m, 1H), 1.62-1.57 (m, 1H), 0.92 (t, J = 7.5 Hz, 3H) ppm. 873 431.35 0.68 874 414.24 0.66 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.21 (s, 1H), 7.74-7.47 (m, 3H), 7.28-7.06 (m, 2H), 6.82 (s, 1H), 3.49 (t, J = 6.4 Hz, 2H), 3.33-3.10 (m, 3H), 2.31 (s, 3H), 1.89 (d, J = 13.2 Hz, 2H), 1.83-1.68 (m, 2H), 1.46 (dd, J = 18.0, 11.4 Hz, 4H) ppm. 875 455.32 0.64 876 416.31 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.19 (s, 1H), 7.69-7.52 (m, 2H), 7.44 (s, 1H), 7.30-7.13 (m, 2H), 7.12-6.67 (m, 1H), 6.63 (s, 1H) ppm. 877 428.31 0.61 878 469.37 2.75 879 469.34 2.34 880 484.35 0.63 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.16 (s, 1H), 7.74-7.58 (m, 2H), 7.25 (td, J = 9.1, 4.6 Hz, 1H), 6.94 (s, 1H), 6.63 (s, 1H), 5.95 (s, 1H), 4.20-4.09 (m, 2H), 3.66-2.84 (m, 16H), 2.19 (s, 3H), 2.08-1.95 (m, 1H) ppm. 881 413.3 2.61 882 457.57 1.84 883 501.23 0.95 1H NMR (300 MHz, DMSO-d6) δ 9.79 (d, J = 12.5 Hz, 1H), 9.21 (s, 1H), 7.66-7.56 (m, 2H), 7.47 (d, J = 19.4 Hz, 2H), 7.32-7.21 (m, 1H), 6.77 (s, 1H), 2.08-1.94 (m, 1H), 0.75 (t, J = 6.7 Hz, 4H) ppm. 884 455.31 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.13 (d, J = 2.8 Hz, 1H), 7.69-7.59 (m, 2H), 6.94 (s, 1H), 6.66 (s, 1H), 6.15 (s, 1H), 4.13 (d, J = 12.5 Hz, 1H), 3.94 (d, J = 16.7 Hz, 2H), 3.70 (dd, J = 12.5, 6.5 Hz, 2H), 3.61 (s, 1H), 3.30 (s, 3H), 2.48 (d, J = 2.6 Hz, 26H), 2.19 (s, 3H), 1.91 (s, 5H), 1.56 (s, 2H) ppm. 885 479.39 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.32-7.17 (m, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.85 (s, 1H), 6.30 (s, 1H), 3.73-3.46 (m, 5H), 3.25-3.17 (m, 1H), 2.36-2.32 (m, 1H), 2.23 (s, 3H), 1.25 (d, J = 5.2 Hz, 2H) ppm. 886 373.05 0.9 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.80-7.57 (m, 1H), 7.48-7.32 (m, 3H), 7.08 (d, J = 3.7 Hz, 1H), 7.03-6.91 (m, 1H), 6.28 (dd, J = 7.3, 1.9 Hz, 1H), 4.89 (tt, J = 4.7, 2.5 Hz, 1H), 4.04-3.66 (m, 4H), 2.29 (d, J = 1.0 Hz, 3H), 2.25-1.99 (m, 2H) ppm. 887 427.4 2.38 888 442.29 0.8 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.16 (s, 1H), 7.67-7.55 (m, 2H), 7.23 (s, 2H), 6.83 (s, 1H), 6.31 (s, 1H), 3.99-3.89 (m, 1H), 3.76 (q, J = 6.8 Hz, 2H), 3.70-3.58 (m, 3H), 3.51-3.40 (m, 2H), 2.68 (td, J = 11.6, 3.2 Hz, 1H), 2.49-2.40 (m, 1H), 2.23 (s, 3H), 2.01-1.89 (m, 1H), 1.89-1.73 (m, 3H) ppm. 889 396.9 2.65 890 411.9 3.07 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.15 (s, 1H), 7.64-7.56 (m, 2H), 7.24 (tt, J = 9.1, 2.1 Hz, 1H), 6.72 (d, J = 12.4 Hz, 2H), 5.82 (s, 1H), 3.90 (dt, J = 10.5, 7.5 Hz, 2H), 3.77 (dd, J = 9.0, 6.4 Hz, 2H), 3.64 (q, J = 7.6 Hz, 2H), 3.34 (dd, J = 8.4, 5.9 Hz, 2H), 2.72-2.60 (m, 1H), 2.20 (s, 3H), 2.07-1.94 (m, 1H), 1.57-1.43 (m, 1H) ppm. 891 469.44 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.27 (d, J = 4.5 Hz, 1H), 9.15 (s, 1H), 7.71-7.60 (m, 2H), 7.25 (tt, J = 9.3, 4.7 Hz, 1H), 7.00 (s, 1H), 6.55 (d, J = 9.3 Hz, 1H), 6.04 (s, 1H), 4.28-4.18 (m, 1H), 3.87-3.80 (m, 2H), 3.77-3.70 (m, 4H), 3.15-3.06 (m, 2H), 2.17 (s, 4H), 2.11-1.99 (m, 2H), 1.93-1.49 (m, 6H) ppm. 892 468.41 0.63 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 2H), 9.41 (s, 1H), 9.16 (s, 1H), 7.70-7.55 (m, 2H), 7.26 (tt, J = 9.2, 2.3 Hz, 1H), 7.14 (s, 1H), 6.94 (s, 1H), 6.38 (s, 1H), 3.37-3.03 (m, 8H), 2.96-2.74 (m, 4H), 2.25 (s, 3H), 2.14-1.92 (m, 2H), 1.74-1.47 (m, 3H) ppm. 893 429.42 0.64 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H), 7.74-7.58 (m, 2H), 7.24 (tt, J = 9.3, 2.3 Hz, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 5.99 (s, 1H), 4.07 (dd, J = 12.7, 3.4 Hz, 1H), 3.94-3.83 (m, 1H), 3.44 (d, J = 12.3 Hz, 2H), 3.21 (ddd, J = 19.5, 13.1, 5.7 Hz, 4H), 2.84 (q, J = 10.8 Hz, 1H), 2.16 (s, 3H), 1.21 (t, J = 7.3 Hz, 3H) ppm. 894 429.33 0.67 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 2H), 9.30 (s, 1H), 9.15 (s, 1H), 7.76-7.54 (m, 2H), 7.25 (tt, J = 9.4, 2.3 Hz, 1H), 6.90 (d, J = 17.2 Hz, 1H), 6.63 (d, J = 11.7 Hz, 1H), 5.95 (s, 1H), 4.21-4.04 (m, 1H), 3.73-3.61 (m, 3H), 3.45-3.39 (m, 3H), 3.32 (d, J = 8.6 Hz, 3H), 3.23-3.08 (m, 1H), 2.19 (s, 2H), 2.08-1.84 (m, 2H) ppm. 895 469.41 0.64 896 457.3 0.65 897 413.36 0.64 898 392.13 0.64 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.5, 1.2 Hz, 2H), 7.51 (dd, J = 11.3, 4.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 6.63 (s, 1H), 6.42 (s, 1H), 4.74 (s, 4H), 3.36 (s, 4H), 2.61 (s, 4H), 2.35 (s, 3H) ppm. 899 483.19 2.14 900 473.36 0.69 901 398.29 3.76 902 429.37 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.17 (s, 1H), 7.70-7.56 (m, 2H), 7.36-7.20 (m, 2H), 6.85 (s, 1H), 6.39 (d, J = 16.1 Hz, 1H), 5.45 (s, 1H), 3.89-3.63 (m, 4H), 3.51 (d, J = 10.4 Hz, 2H), 3.30-3.18 (m, 2H), 3.18-3.09 (m, 1H), 3.04 (t, J = 12.3 Hz, 1H), 2.92 (t, J = 12.0 Hz, 1H), 2.25 (s, 3H), 1.49-1.32 (m, 3H) ppm. 903 457.29 0.68 904 443.42 0.69 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 2H), 9.17 (s, 1H), 7.69-7.57 (m, 2H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.96 (s, 1H), 6.39 (s, 1H), 5.50 (s, 1H), 3.88 (dd, J = 13.2, 2.7 Hz, 1H), 3.77 (s, 2H), 3.70 (dd, J = 13.1, 4.6 Hz, 1H), 3.43-3.15 (m, 4H), 3.07 (q, J = 11.1 Hz, 2H), 2.25 (s, 3H), 1.87-1.63 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H) ppm. 905 453.34 0.88 906 456.39 0.69 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.16 (s, 1H), 7.67-7.56 (m, 2H), 7.32-7.19 (m, 2H), 6.78 (s, 1H), 6.36 (s, 1H), 3.76 (d, J = 6.0 Hz, 3H), 3.64-3.57 (m, 7H), 2.23 (s, 3H), 1.96 (t, J = 4.7 Hz, 2H), 1.67 (d, J = 13.5 Hz, 2H), 1.50 (ddd, J = 14.1, 9.4, 5.4 Hz, 2H) ppm. 907 355 0.89 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.90-8.72 (m, 1H), 7.91-7.78 (m, 2H), 7.66-7.47 (m, 3H), 7.43-7.26 (m, 1H), 6.52 (dd, J = 7.2, 2.0 Hz, 1H), 5.03 (tt, J = 3.8, 1.9 Hz, 1H), 3.99-3.67 (m, 4H), 2.28 (d, J = 2.4 Hz, 3H), 2.24-2.10 (m, 1H), 2.00 (dt, J = 12.1, 5.2 Hz, 1H) ppm. 908 410.08 0.62 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 8.44 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.96-7.76 (m, 3H), 7.28-7.19 (m, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.42 (dd, J = 7.7, 1.5 Hz, 1H), 4.72 (d, J = 6.5 Hz, 4H), 3.64 (s, 1H), 3.19 (s, 4H), 2.58 (s, 4H), 2.39 (s, 3H) ppm. 909 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.34 (s, 1H), 7.67-7.49 (m, 2H), 7.35 (d, J = 2.6 Hz, 1H), 7.29-7.11 (m, 1H), 6.49 (d, J = 2.7 Hz, 1H), 4.81-4.60 (m, 2H), 4.49-4.31 (m, 2H), 4.18 (d, J = 6.8 Hz, 2H), 3.49-3.24 (m, 3H), 2.23 (s, 3H), 2.10 (s, 3H) ppm. 910 363.01 0.81 1H NMR (300 MHz, MeOD + CDCl3) δ 8.67 (s, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.40 (dd, J = 14.3, 6.9 Hz, 2H), 7.06 (s, 1H), 6.83 (s, 1H), 4.28-4.21 (m, 1H), 2.33 (s, 5H), 1.89 (dd, J = 10.2, 7.7 Hz, 2H), 1.71 (dd, J = 11.9, 4.8 Hz, 2H) ppm. 911 455.32 0.63 912 455.31 0.7 913 373 0.9 1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.90 (d, J = 1.9 Hz, 1H), 7.83-7.65 (m, 2H), 7.66-7.47 (m, 2H), 7.20 (tdd, J = 8.5, 2.5, 1.0 Hz, 1H), 6.54 (dd, J = 7.2, 2.0 Hz, 1H), 5.04 (ddt, J = 6.2, 4.1, 1.8 Hz, 1H), 3.98-3.60 (m, 4H), 2.29 (s, 3H), 2.25-2.10 (m, 1H), 2.01 (ddq, J = 12.1, 5.4, 3.6, 2.6 Hz, 1H) ppm. 914 455.4 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.66-7.57 (m, 2H), 7.30-7.19 (m, 1H), 7.16 (s, 1H), 6.95 (s, 1H), 6.39 (s, 1H), 4.31-4.24 (m, 1H), 3.94-3.82 (m, 1H), 3.82-3.69 (m, 3H), 3.66-3.59 (m, 1H), 3.35-3.30 (m, 2H), 3.30-2.96 (m, 5H), 2.25 (s, 3H), 2.16-1.99 (m, 1H), 1.94-1.84 (m, 2H), 1.57-1.51 (m, 1H) ppm. 915 375.93 0.89 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.49 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 17.8 Hz, 1H), 5.93 (d, J = 7.6 Hz, 1H), 5.03 (t, J = 6.3 Hz, 2H), 4.81-4.46 (m, 3H), 4.31 (s, 1H), 2.07 (d, J = 1.5 Hz, 3H) ppm. 916 379.25 0.68 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.15 (s, 1H), 7.61 (dd, J = 6.8, 4.0 Hz, 2H), 7.30-7.19 (m, 1H), 7.16 (d, J = 3.0 Hz, 1H), 6.83 (s, 1H), 6.29 (s, 1H), 5.79-5.72 (m, 1H), 2.23 (s, 3H) ppm. 917 443.39 0.65 918 426.21 1.93 919 455.31 0.71 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.31 (s, 1H), 9.14 (s, 1H), 7.68-7.56 (m, 2H), 7.25 (tt, J = 9.2, 2.4 Hz, 1H), 6.84 (s, 1H), 6.73 (s, 1H), 6.04 (s, 1H), 4.16 (d, J = 6.2 Hz, 1H), 3.99-3.71 (m, 5H), 3.10 (d, J = 7.7 Hz, 3H), 2.25 (s, 3H), 2.19-2.11 (m, 1H), 2.09-1.90 (m, 3H) ppm. 920 455.4 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.13 (d, J = 2.3 Hz, 1H), 7.69-7.53 (m, 2H), 7.22 (tt, J = 8.7, 8.1, 4.1 Hz, 1H), 7.14 (s, 1H), 6.60 (d, J = 10.7 Hz, 1H), 6.04 (d, J = 15.5 Hz, 1H), 4.17-3.63 (m, 7H), 3.43-3.14 (m, 3H), 2.23 (s, 3H), 1.93-1.77 (m, 1H), 1.27 (dd, J = 26.9, 5.8 Hz, 3H) ppm. 921 381.32 2.41 922 423.38 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.64-7.55 (m, 2H), 7.23 (t, J = 8.7 Hz, 1H), 7.17-7.10 (m, 1H), 6.85 (s, 1H), 6.30 (s, 1H), 4.39 (s, 1H), 3.62-3.42 (m, 2H), 2.45-2.41 (m, 2H), 2.23 (s, 3H) ppm. 923 547 0.71 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.75 (d, J = 6.7 Hz, 1H), 7.29 (s, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.14 (s, 1H), 6.82 (tt, J = 8.7, 2.2 Hz, 1H), 6.41 (d, J = 7.1 Hz, 1H), 4.58-3.96 (m, 4H), 3.57-2.53 (m, 9H), 2.38 (s, 3H), 2.12 (s, 9H) ppm. 924 412.31 0.71 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.16 (s, 1H), 7.66-7.57 (m, 2H), 7.22 (tt, J = 9.3, 2.4 Hz, 1H), 7.11 (s, 1H), 6.52 (s, 1H), 5.77 (s, 1H), 3.87 (dd, J = 11.5, 4.5 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H), 3.33 (t, J = 11.8 Hz, 3H), 2.32 (td, J = 12.5, 4.6 Hz, 2H), 2.17 (d, J = 2.9 Hz, 4H), 1.66 (d, J = 12.5 Hz, 2H) ppm. 925 481.87 2.39 926 463.41 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 9.14 (s, 1H), 7.64-7.54 (m, 2H), 7.29-7.17 (m, 1H), 7.11 (s, 1H), 6.85 (s, 1H), 6.29 (s, 1H), 3.99-3.87 (m, 1H), 3.74 (d, J = 11.1 Hz, 1H), 3.24-3.13 (m, 2H), 2.53-2.44 (m, 12H), 2.22 (s, 3H), 1.96 (d, J = 11.2 Hz, 1H), 1.72-1.61 (m, 1H), 1.58-1.28 (m, 1H) ppm. 927 443.9 3.56 928 429.33 0.68 929 378.13 0.66 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.69 (dd, J = 7.6, 1.2 Hz, 2H), 7.51 (dd, J = 11.2, 4.6 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 6.82 (s, 1H), 6.60 (s, 1H), 6.41 (s, 1H), 3.35 (s, 4H), 2.78 (s, 4H), 2.34 (s, 3H), 1.16 (s, 6H) ppm. 930 443.33 0.63 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.28 (s, 1H), 9.15 (s, 1H), 7.71-7.57 (m, 2H), 7.25 (tt, J = 9.3, 2.3 Hz, 1H), 7.00 (d, J = 9.5 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.05 (s, 1H), 3.44 (d, J = 11.5 Hz, 5H), 3.32 (d, J = 3.0 Hz, 3H), 3.27 (q, J = 4.9 Hz, 2H), 3.16-3.02 (m, 2H), 2.17 (s, 3H), 2.03 (s, 2H), 1.67 (q, J = 12.4, 11.9 Hz, 2H) ppm. 931 429.28 0.67 932 402.17 1.93 933 457.33 0.61 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.38 (s, 1H), 9.18 (s, 1H), 7.69-7.54 (m, 2H), 7.34 (s, 1H), 7.25 (tt, J = 9.3, 2.3 Hz, 1H), 6.90 (s, 1H), 6.45 (s, 1H), 3.75 (t, J = 5.0 Hz, 4H), 3.29 (q, J = 5.1 Hz, 3H), 3.04 (t, J = 10.8 Hz, 2H), 2.81 (d, J = 4.7 Hz, 6H), 2.25 (s, 3H), 2.07-1.94 (m, 2H), 1.66 (d, J = 9.5 Hz, 2H) ppm. 934 443.37 1.87 935 443.24 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.64-7.54 (m, 2H), 7.29-7.17 (m, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.86 (s, 1H), 6.44-5.92 (m, 2H), 2.79 (td, J = 15.9, 4.2 Hz, 2H), 2.23 (s, 3H) ppm. 936 455.04 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.43 (s, 1H), 9.17 (s, 1H), 7.67-7.51 (m, 2H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.96 (s, 1H), 6.40 (s, 1H), 3.85 (t, J = 7.9 Hz, 1H), 3.82-3.71 (m, 2H), 3.71-3.52 (m, 3H), 3.48-3.40 (m, 2H), 3.30-3.10 (m, 3H), 3.10-3.01 (m, 2H), 2.75-2.60 (m, 1H), 2.25 (s, 3H), 2.18-2.04 (m, 1H), 1.70-1.56 (m, 1H) ppm. 937 400.27 1.99 938 455.33 2.08 939 469.4 0.8 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.16 (d, J = 2.2 Hz, 1H), 7.70-7.58 (m, 2H), 7.25 (tt, J = 9.3, 2.2 Hz, 1H), 7.07 (s, 1H), 6.62 (s, 1H), 6.15 (s, 1H), 4.04-3.80 (m, 3H), 3.80-3.66 (m, 2H), 3.44-3.05 (m, 6H), 2.19 (s, 3H), 2.11 (d, J = 12.1 Hz, 1H), 1.92-1.76 (m, 1H), 1.70-1.47 (m, 2H), 1.40-1.09 (m, 3H) ppm. 940 447.17 1.65 941 457.38 0.69 942 356.17 1.83 943 457.14 0.71 1H NMR (300 MHz, Chloroform-d) δ 8.38 (s, 1H), 7.44 (s, 1H), 7.41-7.28 (m, 2H), 6.97-6.70 (m, 1H), 6.35-6.04 (m, 1H), 3.90-3.61 (m, 1H), 3.61-3.21 (m, 2H), 2.96-2.45 (m, 9H), 2.47-2.14 (m, 4H), 2.14-1.86 (m, 2H) ppm. 944 468.38 0.58 945 482.38 0.58 946 445.31 0.61 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 3.3 Hz, 1H), 9.15 (s, 1H), 7.71-7.59 (m, 2H), 7.24 (t, J = 9.3 Hz, 1H), 6.97 (d, J = 15.4 Hz, 1H), 6.56 (d, J = 15.2 Hz, 1H), 5.99 (d, J = 7.5 Hz, 1H), 4.36 (s, 1H), 4.14-3.97 (m, 3H), 3.90-3.79 (m, 1H), 3.67-3.60 (m, 3H), 3.24 (d, J = 6.6 Hz, 2H), 2.17 (s, 3H) ppm. 947 407.35 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.66-7.53 (m, 2H), 7.23 (t, J = 8.5 Hz, 1H), 7.15 (s, 1H), 6.85 (s, 1H), 6.30 (s, 1H), 2.37 (q, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H) ppm. 948 413.23 0.58 1H NMR (400 MHz, Methanol-d4) δ 8.96 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.71-7.60 (m, 2H), 7.39 (dd, J = 2.0, 0.9 Hz, 1H), 7.12 (d, J = 1.7 Hz, 1H), 6.98 (tt, J = 9.0, 2.3 Hz, 1H), 3.90 (s, 2H), 3.89-3.73 (m, 1H), 2.99 (s, 6H), 2.66 (s, 1H), 2.61-2.47 (m, 1H), 2.51 (s, 4H), 2.43 (s, 3H) ppm. 949 470.91 2.68 950 432.39 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.19 (s, 1H), 7.70-7.58 (m, 2H), 7.46 (s, 1H), 7.26 (tt, J = 9.2, 2.3 Hz, 1H), 7.06 (s, 1H), 6.62 (s, 1H), 4.64-4.56 (m, 1H), 4.52-4.45 (m, 1H), 3.62-3.52 (m, 4H), 3.27-3.07 (m, 2H), 2.28 (s, 3H), 2.10-1.98 (m, 2H), 1.81-1.65 (m, 2H) ppm. 951 441.37 0.64 952 356.98 0.8 1H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.17-9.00 (m, 2H), 8.68 (d, J = 2.6 Hz, 1H), 8.59 (dd, J = 2.6, 1.4 Hz, 1H), 7.56 (dd, J = 6.9, 1.9 Hz, 1H), 6.57 (dd, J = 7.3, 2.0 Hz, 1H), 5.04 (tt, J = 4.0, 2.1 Hz, 1H), 3.97-3.61 (m, 4H), 2.31 (s, 3H), 2.27-2.11 (m, 1H), 2.01 (dt, J = 12.5, 5.5 Hz, 1H) ppm. 953 390.01 0.72 1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.6 Hz, 1H), 7.66 (dd, J = 8.4, 2.6 Hz, 2H), 7.32 (dd, J = 6.8, 2.9 Hz, 1H), 7.24 (tt, J = 7.0, 3.3 Hz, 1H), 5.99 (dd, J = 5.6, 2.9 Hz, 1H), 5.66 (d, J = 5.2 Hz, 1H), 4.01-3.78 (m, 3H), 3.63-3.34 (m, 1H), 2.15 (t, J = 2.3 Hz, 4H), 1.80 (d, J = 5.5 Hz, 1H) ppm. 954 484.35 0.62 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.17 (s, 1H), 7.67-7.57 (m, 2H), 7.29-7.19 (m, 2H), 6.84 (s, 1H), 6.34 (s, 1H), 4.01-3.93 (m, 2H), 3.89 (d, J = 7.6 Hz, 2H), 3.70-3.61 (m, 8H), 2.89 (s, 2H), 2.79 (s, 3H), 2.71 (td, J = 12.1, 3.5 Hz, 2H), 2.46 (d, J = 10.8 Hz, 1H), 2.24 (s, 3H) ppm. 955 427.04 0.66 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.80 (d, J = 6.7 Hz, 1H), 7.53-7.43 (m, 3H), 7.14-7.02 (m, 1H), 6.92 (d, J = 3.9 Hz, 1H), 6.42 (d, J = 6.1 Hz, 1H), 4.74 (s, 4H), 3.67 (s, 1H), 3.22 (s, 4H), 2.60 (s, 3H), 2.38 (s, 3H) ppm. 956 467.94 2.38 957 443.42 0.66 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.42 (s, 1H), 9.16 (s, 1H), 7.66-7.55 (m, 2H), 7.25 (tt, J = 9.3, 2.3 Hz, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 6.39 (s, 1H), 5.51 (s, 1H), 3.93-3.81 (m, 1H), 3.74 (dd, J = 21.8, 12.5 Hz, 2H), 3.65-3.52 (m, 2H), 3.29-3.12 (m, 4H), 3.06 (t, J = 11.9 Hz, 2H), 2.25 (s, 3H), 1.51-1.36 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H) ppm. 958 416.34 2.77 959 424.33 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.15 (s, 1H), 7.65-7.56 (m, 2H), 7.23 (t, J = 8.6 Hz, 1H), 7.14 (s, 1H), 6.90 (s, 1H), 6.33 (s, 1H), 2.24 (s, 3H) ppm. 960 443.37 0.7 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.68-7.58 (m, 2H), 7.25 (tt, J = 9.4, 2.3 Hz, 1H), 6.94 (s, 1H), 6.61 (s, 1H), 6.08 (s, 1H), 3.89-3.74 (m, 5H), 3.36-3.16 (m, 6H), 2.18 (s, 3H), 1.56 (dq, J = 14.3, 7.3 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H) ppm. 961 447.34 0.76 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.15 (s, 1H), 7.66-7.55 (m, 2H), 7.24 (tt, J = 9.2, 2.3 Hz, 1H), 7.20-7.08 (m, 1H), 6.90 (s, 1H), 6.35 (s, 1H), 2.25 (s, 3H), 2.07-1.95 (m, 1H), 0.81-0.67 (m, 4H) ppm. 962 458.37 0.69 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.08 (s, 1H), 7.58-7.47 (m, 2H), 7.35 (s, 1H), 7.16 (td, J = 9.2, 4.7 Hz, 1H), 6.94 (s, 1H), 6.50 (s, 1H), 3.52-3.43 (m, 9H), 3.11-3.00 (m, 2H), 2.17 (s, 3H), 1.97-1.86 (m, 2H), 1.59 (d, J = 11.8 Hz, 2H), 0.99 (t, J = 7.0 Hz, 3H) ppm. 963 461.06 0.7 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H), 7.46 (d, J = 7.9 Hz, 3H), 6.85 (t, J = 9.3 Hz, 1H), 6.17 (d, J = 7.4 Hz, 1H), 4.01 (s, 4H), 3.71 (s, 3H), 2.34 (s, 3H), 1.04 (s, 4H) ppm. 964 429.35 2.62 965 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.31 (s, 1H), 7.73-7.52 (m, 2H), 7.41-7.31 (m, 1H), 7.29-7.11 (m, 1H), 6.46 (s, 1H), 4.64 (s, 2H), 3.62-3.39 (m, 5H), 3.31 (t, J = 6.8 Hz, 2H), 2.22 (s, 3H), 2.10 (s, 3H), 1.96-1.61 (m, 4H) ppm. 966 390.15 0.56 1H NMR (300 MHz, CDCl3) δ 9.02 (d, J = 2.6 Hz, 1H), 8.63 (dt, J = 4.8, 1.3 Hz, 1H), 8.37 (d, J = 1.0 Hz, 1H), 8.02 (ddt, J = 8.2, 2.6, 1.3 Hz, 1H), 7.50 (dd, J = 8.3, 4.7 Hz, 1H), 6.81-6.50 (m, 3H), 5.94 (s, 1H), 3.99 (s, 4H), 3.37 (s, 4H), 0.99-0.66 (m, 6H) ppm. 967 391.14 0.61 1H NMR (300 MHz, CDCl3) δ 9.19 (d, J = 1.5 Hz, 1H), 9.03-8.71 (m, 1H), 8.57 (s, 1H), 8.48-8.16 (m, 1H), 7.28 (d, J = 1.7 Hz, 1H), 6.74 (dd, J = 4.2, 2.1 Hz, 2H), 6.63 (s, 1H), 5.96 (s, 1H), 4.00 (s, 4H), 3.38 (s, 4H), 2.46-2.09 (m, 4H), 0.96 (dd, J = 6.0, 4.1 Hz, 6H) ppm. 968 441.37 0.62 969 390.01 0.91 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.74 (d, J = 7.3 Hz, 1H), 6.96 (s, 1H), 6.82 (s, 1H), 6.07 (d, J = 7.5 Hz, 1H), 4.82 (t, J = 6.6 Hz, 2H), 4.69 (t, J = 6.3 Hz, 2H), 4.55-4.39 (m, 1H), 2.82 (s, 3H), 2.35 (s, 2H) ppm. 970 414.21 1.89 971 414.46 3.65 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.38 (s, 1H), 7.82-7.47 (m, 2H), 7.39-7.07 (m, 2H), 6.51-6.22 (m, 1H), 5.06-4.85 (m, 1H), 4.61-4.43 (m, 1H), 4.34-4.17 (m, 1H), 4.16-4.02 (m, 1H), 3.87-3.67 (m, 1H), 2.23 (s, 3H), 2.10 (s, 3H), 1.78 (s, 3H) ppm. 972 442.25 0.81 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.16 (s, 1H), 7.70-7.51 (m, 2H), 7.33-7.15 (m, 2H), 6.83 (s, 1H), 6.37 (s, 1H), 3.96 (dd, J = 11.2, 3.0 Hz, 1H), 3.83 (q, J = 6.5 Hz, 1H), 3.77-3.69 (m, 2H), 3.55-3.50 (m, 2H), 3.46 (d, J = 11.7 Hz, 2H), 2.71 (td, J = 12.0, 3.4 Hz, 1H), 2.62 (t, J = 11.1 Hz, 1H), 2.24 (s, 3H), 1.98-1.62 (m, 4H) ppm. 973 443.3 0.64 974 456.91 2.8 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.16 (s, 1H), 7.74-7.56 (m, 2H), 7.25 (t, J = 9.5 Hz, 1H), 6.97 (d, J = 3.7 Hz, 1H), 6.62 (d, J = 7.0 Hz, 1H), 6.04 (d, J = 13.3 Hz, 1H), 4.01-3.77 (m, 3H), 3.48-3.15 (m, 6H), 3.02-2.90 (m, 1H), 2.20 (s, 3H), 1.93-1.76 (m, 1H), 1.76-1.61 (m, 1H), 1.14 (t, J = 6.7 Hz, 3H), 0.93 (dt, J = 19.3, 7.4 Hz, 3H) ppm. 975 440.4 0.63 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.15 (s, 1H), 7.64-7.55 (m, 2H), 7.24 (tt, J = 9.3, 2.4 Hz, 1H), 6.77-6.66 (m, 2H), 5.82 (s, 1H), 3.93 (t, J = 7.1 Hz, 2H), 3.77-3.54 (m, 5H), 3.12-2.92 (m, 4H), 2.79 (s, 3H), 2.36-2.23 (m, 2H), 2.20 (s, 3H) ppm. 976 414.31 0.65 977 425.15 0.68 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J = 1.8 Hz, 1H), 7.55 (ddd, J = 10.9, 6.8, 2.6 Hz, 1H), 7.47-7.28 (m, 2H), 6.73-6.53 (m, 3H), 5.93 (t, J = 1.9 Hz, 1H), 3.97 (d, J = 1.9 Hz, 4H), 3.37 (s, 4H), 2.41-2.08 (m, 1H), 0.96 (dd, J = 6.3, 1.8 Hz, 6H) ppm. 978 391 0.91 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.89 (d, J = 1.7 Hz, 1H), 7.96 (ddd, J = 12.0, 7.2, 2.1 Hz, 1H), 7.77-7.59 (m, 2H), 7.51 (dd, J = 7.0, 1.9 Hz, 1H), 6.53 (dd, J = 7.2, 2.0 Hz, 1H), 5.03 (ddt, J = 6.2, 4.0, 1.7 Hz, 1H), 3.98-3.58 (m, 4H), 2.28 (s, 3H), 2.25-2.10 (m, 1H), 2.09-1.86 (m, 1H) ppm. 979 435.45 0.66 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.14 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.23 (t, J = 9.3 Hz, 1H), 7.13 (s, 1H), 6.87 (s, 1H), 6.31 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 3.46 (t, J = 6.2 Hz, 1H), 2.23 (s, 3H) ppm. 980 357.97 0.9 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.19 (d, J = 2.1 Hz, 1H), 7.79-7.46 (m, 2H), 7.35-7.21 (m, 1H), 7.17 (s, 1H), 6.14 (s, 1H), 4.11 (dd, J = 6.9, 2.1 Hz, 2H), 2.27 (s, 3H), 1.38-1.19 (m, 1H), 0.62-0.44 (m, 2H), 0.39-0.23 (m, 2H) ppm. 981 412.35 0.69 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.17 (s, 1H), 7.64-7.55 (m, 2H), 7.38 (s, 1H), 7.24 (tt, J = 9.3, 2.4 Hz, 1H), 6.78 (s, 1H), 6.40 (s, 1H), 4.39 (q, J = 6.9 Hz, 1H), 3.90 (t, J = 7.8 Hz, 1H), 3.85 (dd, J = 8.3, 5.7 Hz, 1H), 3.65 (dd, J = 8.3, 3.3 Hz, 1H), 2.95 (d, J = 10.9 Hz, 1H), 2.40-2.31 (m, 1H), 2.23 (s, 3H), 1.88-1.72 (m, 2H), 1.64-1.43 (m, 2H) ppm. 982 380.24 0.74 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 9.15 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.30-7.17 (m, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.90 (s, 1H), 6.32 (s, 1H), 2.24 (s, 3H) ppm. 983 455.35 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.30 (s, 1H), 9.15 (s, 1H), 7.61 (h, J = 5.5 Hz, 2H), 7.25 (tt, J = 9.3, 2.2 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.66 (s, 1H), 5.94 (s, 1H), 3.99 (d, J = 12.5 Hz, 2H), 3.71 (t, J = 12.0 Hz, 4H), 3.37 (td, J = 8.3, 3.3 Hz, 2H), 3.29 (dd, J = 12.5, 7.5 Hz, 3H), 3.20-3.01 (m, 3H), 2.79 (q, J = 7.5 Hz, 1H), 2.21 (s, 4H), 1.86-1.72 (m, 1H) ppm. 984 469.34 2.27 985 443.32 2.74 986 425.41 0.69 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.66-7.58 (m, 2H), 7.24 (tt, J = 9.2, 2.2 Hz, 1H), 7.03 (t, J = 2.1 Hz, 1H), 6.67 (s, 1H), 6.03 (s, 1H), 4.09-4.00 (m, 1H), 3.72-3.58 (m, 3H), 3.54-3.42 (m, 3H), 3.28 (q, J = 8.2 Hz, 1H), 3.23-3.13 (m, 2H), 2.23 (s, 3H), 2.19 (dd, J = 12.8, 8.0 Hz, 1H), 2.12-2.02 (m, 2H), 1.95-1.84 (m, 2H) ppm. 987 469.94 2.41 988 469.37 0.59 989 462.99 0.66 1H NMR (300 MHz, DMSO) δ 9.16 (s, 1H), 8.82 (s, 1H), 7.76-7.55 (m, 2H), 7.50 (d, J = 7.1 Hz, 1H), 7.33-7.14 (m, 1H), 6.43 (d, J = 6.5 Hz, 1H), 4.62-4.35 (m, 2H), 3.72-3.41 (m, 3H), 3.30-2.53 (m, 9H), 2.47-2.37 (m, 1H), 2.30 (d, J = 17.9 Hz, 3H) ppm. 990 429.35 2.6 991 482.87 2.97 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.17 (s, 1H), 7.67-7.58 (m, 2H), 7.31-7.23 (m, 1H), 7.20 (s, 1H), 6.92 (s, 1H), 6.38 (s, 1H), 3.71-3.66 (m, 3H), 3.65-3.60 (m, 2H), 3.40 (td, J = 11.4, 2.6 Hz, 2H), 3.14 (d, J = 17.0 Hz, 4H), 2.98-2.87 (m, 1H), 2.25 (s, 3H), 1.68-1.51 (m, 4H) ppm. 992 449.2 1.73 993 413.43 2.26 994 433.38 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.23 (t, J = 9.2 Hz, 1H), 7.14 (s, 1H), 6.85 (s, 1H), 6.30 (s, 1H), 2.81-2.69 (m, 1H), 2.22 (s, 3H), 1.99 (d, J = 7.8 Hz, 2H), 1.82 (t, J = 9.5 Hz, 2H), 1.66 (d, J = 9.7 Hz, 2H) ppm. 995 429.35 2.63 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.43 (s, 1H), 9.17 (s, 1H), 7.68-7.56 (m, 2H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 6.39 (s, 1H), 5.55 (s, 1H), 4.18-4.06 (m, 1H), 3.73 (dd, J = 21.3, 12.6 Hz, 2H), 3.59 (d, J = 11.5 Hz, 2H), 3.27-3.11 (m, 4H), 3.11-3.01 (m, 2H), 2.25 (s, 3H), 1.14 (d, J = 6.1 Hz, 3H) ppm. 996 411.29 0.64 997 436.18 0.67 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.26 (d, J = 6.8 Hz, 2H), 7.12 (s, 1H), 6.80 (s, 2H), 6.67 (s, 1H), 6.43 (s, 1H), 4.74 (s, 4H), 2.36 (s, 3H) ppm. 998 445.04 0.68 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.59 (ddd, J = 10.8, 6.8, 2.6 Hz, 1H), 7.47-7.38 (m, 1H), 7.33 (dd, J = 9.3, 8.1 Hz, 1H), 6.94 (d, J = 4.0 Hz, 1H), 6.42 (dd, J = 7.7, 1.6 Hz, 1H), 4.73 (d, J = 4.8 Hz, 4H), 3.65 (t, J = 10.4 Hz, 1H), 3.20 (s, 4H), 2.59 (s, 4H), 2.38 (s, 3H) ppm. 999 388.08 0.91 1H NMR (300 MHz, DMSO-d6) δ 9.75 (d, J = 2.1 Hz, 1H), 9.20 (d, J = 2.1 Hz, 1H), 7.75-7.60 (m, 2H), 7.33-7.19 (m, 1H), 7.12 (s, 1H), 6.12 (s, 1H), 5.13-4.98 (m, 1H), 4.03-3.89 (m, 1H), 3.75-3.61 (m, 1H), 3.55-3.36 (m, 2H), 2.26 (s, 3H), 2.14-1.99 (m, 1H), 1.85-1.48 (m, 3H) ppm. 1001 456.94 2.75 1002 355.05 0.89 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.86-7.67 (m, 1H), 7.68-7.57 (m, 2H), 7.44 (dd, J = 8.6, 7.1 Hz, 2H), 7.37-7.22 (m, 1H), 6.99 (s, 1H), 6.26 (dd, J = 7.3, 1.9 Hz, 1H), 4.89 (dq, J = 4.9, 2.6 Hz, 1H), 3.98-3.71 (m, 4H), 2.28 (s, 3H), 2.16-2.00 (m, 2H) ppm. 1003 443.39 0.64 1004 399.14 2.04 1005 457.37 2.85 1006 399.94 2.68 1007 473.12 0.72 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.42 (d, J = 6.8 Hz, 1H), 6.11 (d, J = 7.3 Hz, 1H), 4.12 (d, J = 5.6 Hz, 1H), 3.94 (s, 4H), 3.56 (s, 2H), 3.21 (q, J = 8.6 Hz, 1H), 2.89 (s, 3H), 2.46 (s, 1H), 2.24 (d, J = 2.2 Hz, 3H), 2.14-1.76 (m, 4H) ppm. 1008 400.31 2.1 1009 391.05 0.91 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 7.68-7.59 (m, 1H), 7.51 (ddd, J = 10.8, 6.8, 2.6 Hz, 1H), 7.39-7.29 (m, 1H), 7.29-7.21 (m, 1H), 7.10 (d, J = 3.5 Hz, 1H), 6.28 (dd, J = 7.3, 1.9 Hz, 1H), 4.89 (tt, J = 4.9, 2.6 Hz, 1H), 4.03-3.67 (m, 4H), 2.29 (d, J = 1.0 Hz, 3H), 2.19-2.04 (m, 2H) ppm. 1010 441.3 0.67 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.37 (s, 1H), 9.15 (s, 1H), 7.69-7.54 (m, 2H), 7.23 (tt, J = 9.2, 2.3 Hz, 1H), 7.01 (s, 1H), 6.66 (s, 1H), 6.08-5.94 (m, 2H), 4.54 (d, J = 6.9 Hz, 1H), 3.79 (d, J = 5.6 Hz, 2H), 3.75-3.65 (m, 2H), 3.65-3.55 (m, 2H), 3.25 (s, 2H), 3.11 (dd, J = 9.6, 6.5 Hz, 1H), 2.22 (s, 3H), 1.98 (d, J = 61.0 Hz, 4H) ppm. 1011 443.37 0.69 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.46 (s, 1H), 9.18 (s, 1H), 7.70-7.54 (m, 2H), 7.37-7.19 (m, 2H), 6.86 (d, J = 11.0 Hz, 1H), 6.39 (d, J = 16.7 Hz, 1H), 3.87-3.57 (m, 5H), 3.52 (s, 2H), 3.35 (s, 3H), 3.26 (d, J = 10.8 Hz, 2H), 3.07-2.96 (m, 1H), 2.93-2.84 (m, 1H), 2.25 (s, 3H), 1.38 (d, J = 6.3 Hz, 2H) ppm. 1012 455.31 0.71 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.13 (s, 1H), 7.73-7.51 (m, 3H), 7.25 (tt, J = 9.2, 2.5 Hz, 2H), 6.84 (s, 1H), 6.73 (s, 1H), 6.04 (s, 1H), 4.16 (q, J = 6.5 Hz, 2H), 4.02-3.67 (m, 7H), 3.18-3.03 (m, 4H), 2.25 (s, 3H), 2.19-2.12 (m, 1H), 2.07-1.92 (m, 3H) ppm. 1014 456.3 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.19 (s, 1H), 7.71-7.58 (m, 2H), 7.46 (s, 1H), 7.27 (tt, J = 9.4, 2.2 Hz, 1H), 7.07 (s, 1H), 6.63 (s, 1H), 4.35-4.24 (m, 1H), 3.70-3.56 (m, 7H), 3.28-3.05 (m, 2H), 2.28 (s, 3H), 2.07-1.92 (m, 3H), 1.78-1.59 (m, 2H) ppm. 1015 443.33 0.61 1016 390.06 0.78 1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 7.74-7.50 (m, 2H), 7.25 (tt, J = 9.3, 2.3 Hz, 1H), 7.11 (dd, J = 6.8, 2.9 Hz, 1H), 5.90 (s, 1H), 5.82 (dd, J = 5.6, 2.8 Hz, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.45 (dd, J = 5.7, 1.9 Hz, 2H), 2.14 (t, J = 2.3 Hz, 3H), 1.62 (d, J = 2.2 Hz, 3H) ppm. 1017 457.35 0.65 1018 429.3 0.61 1019 427.94 2.87 1020 441.37 0.63 1021 404.1 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 7.74-7.55 (m, 2H), 7.35 (dd, J = 7.0, 2.8 Hz, 1H), 7.33-7.13 (m, 1H), 6.03 (dd, J = 5.8, 2.8 Hz, 1H), 5.33 (d, J = 7.7 Hz, 1H), 3.89 (d, J = 11.5 Hz, 2H), 3.52-3.32 (m, 4H), 2.13 (d, J = 2.3 Hz, 3H), 1.94 (d, J = 13.0 Hz, 2H), 1.51-1.27 (m, 2H) ppm. 1022 410.03 0.55 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J = 2.4 Hz, 1H), 8.64 (dd, J = 4.7, 1.4 Hz, 1H), 8.40 (s, 1H), 8.03 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.48 (dd, J = 8.3, 4.8 Hz, 1H), 7.05 (s, 1H), 6.42 (d, J = 7.6 Hz, 1H), 4.72 (d, J = 6.5 Hz, 4H), 3.65 (d, J = 5.7 Hz, 1H), 3.19 (s, 4H), 2.58 (s, 4H), 2.38 (s, 3H) ppm. 1023 469.32 0.6 1024 457.33 2.63 1025 482.38 0.57 1026 429.36 2.78 1H NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1H), 9.10-8.95 (m, 1H), 7.62-7.44 (m, 3H), 7.22-7.09 (m, 0H), 7.01 (tt, J = 9.0, 2.3 Hz, 2H), 4.32 (s, 0H), 4.25-4.20 (m, 1H), 4.01 (s, 1H), 3.89-3.72 (m, 3H), 3.66 (s, 6H), 3.61 (s, 1H), 3.45 (s, 1H), 3.35 (s, 2H), 3.38-3.29 (m, 1H), 3.18-3.03 (m, 2H), 3.06-2.98 (m, 6H), 2.66 (s, 7H), 2.46-2.29 (m, 3H), 2.33 (s, 4H), 2.18 (s, 2H), 2.08 (s, 3H) ppm. 1027 455.37 0.64 1028 391.05 0.93 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.74-7.60 (m, 1H), 7.27-7.19 (m, 1H), 7.04 (d, J = 3.7 Hz, 1H), 6.73 (tt, J = 8.7, 2.3 Hz, 1H), 6.29 (dd, J = 7.3, 2.0 Hz, 1H), 4.90 (tt, J = 4.9, 2.6 Hz, 1H), 3.99-3.76 (m, 4H), 2.30 (d, J = 1.0 Hz, 3H), 2.22-1.97 (m, 2H) ppm. 1029 400.26 2.14 1030 429.9 3.22 1031 413.3 0.65 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.17 (s, 1H), 7.69-7.62 (m, 2H), 7.30-7.19 (m, 2H), 7.17 (s, 1H), 6.67 (s, 1H), 6.15 (s, 1H), 4.17 (t, J = 8.3 Hz, 2H), 3.54 (dd, J = 9.6, 5.3 Hz, 2H), 2.88-2.80 (m, 1H), 2.19 (s, 3H), 1.72 (s, 3H) ppm. 1032 434.23 0.82 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.21 (d, J = 1.2 Hz, 1H), 7.93-7.06 (m, 5H), 6.77-6.55 (m, 1H) ppm. 1033 459.33 2.6 1034 389.16 0.66 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 2.0 Hz, 1H), 7.79-7.63 (m, 2H), 7.53 (td, J = 7.9, 2.0 Hz, 2H), 7.47-7.33 (m, 1H), 6.78-6.68 (m, 2H), 6.67-6.48 (m, 1H), 5.92 (d, J = 1.9 Hz, 1H), 3.98 (d, J = 2.1 Hz, 4H), 3.37 (d, J = 2.1 Hz, 4H), 2.39-2.12 (m, 4H), 0.97 (dd, J = 6.2, 2.1 Hz, 6H) ppm. 1035 398.24 0.72 1H NMR (400 MHz, Methanol-d4) δ 8.94 (s, 1H), 8.02 (s, 1H), 7.62-7.55 (m, 3H), 7.38 (s, 1H), 7.10 (s, 1H), 7.00 (t, J = 9.1 Hz, 2H), 4.19-4.12 (m, 3H), 3.83 (d, J = 4.4 Hz, 5H), 2.99 (s, 0H), 2.65 (s, 1H), 2.44 (s, 4H), 1.08 (t, J = 3.6 Hz, 3H), 0.96-0.88 (m, 3H) ppm. 1036 415.34 2.6 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.42 (s, 1H), 9.16 (s, 1H), 7.72-7.56 (m, 2H), 7.30-7.19 (m, 1H), 7.15 (s, 1H), 6.95 (s, 1H), 6.39 (s, 1H), 5.44 (s, 1H), 3.88-3.67 (m, 4H), 3.59 (d, J = 12.0 Hz, 2H), 3.30-3.15 (m, 4H), 3.07 (t, J = 12.5 Hz, 2H), 2.25 (s, 3H) ppm. 1037 420.31 1.93 1038 438.67 4.68 1039 406.17 0.65 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.76-7.64 (m, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 6.81 (s, 1H), 6.62 (s, 1H), 6.40 (s, 1H), 4.08-3.73 (m, 4H), 3.33 (s, 4H), 2.72 (d, J = 29.0 Hz, 4H), 2.34 (s, 3H), 2.20-1.92 (m, 2H) ppm. 1040 441.32 2.64 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 2H), 9.38 (s, 1H), 9.17 (s, 1H), 7.73-7.52 (m, 3H), 7.25 (t, J = 9.3 Hz, 1H), 7.03 (d, J = 13.4 Hz, 1H), 6.65 (d, J = 20.3 Hz, 1H), 6.00 (d, J = 12.0 Hz, 1H), 5.61 (s, 1H), 4.55-4.36 (m, 2H), 4.15-3.98 (m, 2H), 3.78-3.60 (m, 3H), 3.31-3.07 (m, 3H), 2.35-2.09 (m, 5H) ppm. 1041 483.31 0.86 1H NMR (300 MHz, DMSO-d6) δ 9.64 (d, J = 12.7 Hz, 1H), 9.23-9.11 (m, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.50-7.07 (m, 4H), 6.95-6.78 (m, 1H), 6.68 (s, 1H), 2.11-1.89 (m, 0H), 0.86-0.51 (m, 4H) ppm. 1042 449.5 0.69 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.26-7.20 (m, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 6.30 (s, 1H), 3.87-3.74 (m, 2H), 3.66 (q, J = 8.0 Hz, 1H), 3.58-3.47 (m, 1H), 2.98-2.87 (m, 1H), 2.23 (s, 3H), 2.04-1.93 (m, 1H), 1.79-1.73 (m, 1H) ppm. 1043 433.03 0.67 1H NMR (300 MHz, CDCl3) δ 8.43-8.19 (m, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.27 (s, 1H), 6.96 (d, J = 4.1 Hz, 1H), 6.81 (dt, J = 7.1, 4.6 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 3.69 (t, J = 5.3 Hz, 2H), 3.15 (t, J = 4.7 Hz, 4H), 2.74 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 5.4 Hz, 2H), 2.39 (s, 3H) ppm. 1044 421.4 0.71 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.15 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.33-7.19 (m, 1H), 7.15 (d, J = 2.2 Hz, 1H), 6.90 (s, 1H), 6.34 (s, 1H), 2.24 (s, 3H), 2.04 (s, 3H) ppm. 1045 469.41 0.59 1046 483.4 0.64 1047 482.38 0.58 1048 441.99 2.07 1049 347.08 0.67 1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.81 (s, 1H), 7.78-7.69 (m, 2H), 7.56-7.46 (m, 2H), 7.40-7.32 (m, 1H), 7.21 (s, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.57 (d, J = 1.3 Hz, 1H), 3.51 (s, 1H), 2.37 (s, 3H), 2.27 (d, J = 1.3 Hz, 3H) ppm. 1050 443.33 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.25 (s, 1H), 9.14 (s, 1H), 7.66 (dt, J = 7.3, 3.5 Hz, 2H), 7.24 (tt, J = 9.3, 2.5 Hz, 1H), 6.95 (d, J = 11.7 Hz, 1H), 6.54 (s, 1H), 6.00 (s, 1H), 3.76-3.61 (m, 3H), 3.35-3.05 (m, 6H), 2.94-2.80 (m, 1H), 2.63 (q, J = 10.4 Hz, 1H), 2.18 (s, 3H), 1.99 (dd, J = 34.4, 13.6 Hz, 2H), 1.79 (d, J = 14.3 Hz, 2H), 1.49-1.29 (m, 1H) ppm. 1051 448.31 2.45 1052 355.05 0.88 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.81-7.69 (m, 1H), 7.68-7.58 (m, 2H), 7.55-7.38 (m, 2H), 7.37-7.29 (m, 1H), 7.01 (d, J = 3.7 Hz, 1H), 6.26 (dd, J = 7.4, 1.9 Hz, 1H), 4.89 (tt, J = 4.7, 2.5 Hz, 1H), 4.03-3.70 (m, 4H), 2.29 (d, J = 1.0 Hz, 3H), 2.19-1.95 (m, 2H) ppm. 1053 391.09 0.93 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 7.74 (dd, J = 7.1, 2.0 Hz, 1H), 7.32-7.28 (m, 1H), 7.14 (d, J = 3.7 Hz, 1H), 6.82 (tt, J = 8.7, 2.3 Hz, 1H), 6.38 (dd, J = 7.3, 1.9 Hz, 1H), 4.99 (tt, J = 5.0, 2.7 Hz, 1H), 2.39 (s, 3H), 2.33-2.09 (m, 2H) ppm. 1054 469.32 0.58 1H NMR (400 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.04 (d, J = 9.9 Hz, 1H), 7.69-7.61 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.10 (s, 0H), 7.03-6.93 (m, 1H), 4.27 (s, 1H), 3.89 (s, 2H), 3.84 (d, J = 4.3 Hz, 1H), 3.67-3.55 (m, 1H), 3.51 (s, 1H), 3.24 (dd, J = 20.5, 11.6 Hz, 1H), 2.66 (s, 1H), 2.54 (s, 2H), 2.52 (s, 0H), 2.43 (s, 3H), 2.36-2.24 (m, 1H), 2.13 (s, 1H), 1.95-1.82 (m, 2H), 1.75 (t, J = 13.3 Hz, 1H) ppm. 1055 391.05 0.91 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.72-7.61 (m, 1H), 7.51 (ddd, J = 10.8, 6.8, 2.6 Hz, 1H), 7.33 (dddd, J = 8.9, 4.0, 2.6, 1.5 Hz, 1H), 7.30-7.21 (m, 1H), 7.09 (d, J = 3.7 Hz, 1H), 6.28 (dd, J = 7.3, 1.9 Hz, 1H), 4.89 (tt, J = 5.0, 2.6 Hz, 1H), 4.06-3.69 (m, 4H), 2.29 (d, J = 1.0 Hz, 3H), 2.21-2.00 (m, 2H) ppm. 1056 457.38 0.7 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.17 (s, 1H), 7.68-7.56 (m, 2H), 7.33-7.16 (m, 2H), 6.85 (s, 1H), 6.43-6.29 (m, 1H), 5.55 (s, 1H), 4.20-3.98 (m, 2H), 3.82-3.64 (m, 2H), 3.32-3.17 (m, 2H), 3.17-3.01 (m, 2H), 2.25 (s, 3H), 2.12-1.83 (m, 2H), 1.82-1.67 (m, 1H), 1.17 (d, J = 6.1 Hz, 3H), 1.03 (q, J = 7.5 Hz, 3H) ppm. 1057 398.3 0.71 1058 333.99 0.82 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.33 (s, 1H), 9.06 (s, 1H), 7.95-7.84 (m, 2H), 7.75 (s, 1H), 7.54 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 1.9 Hz, 2H), 2.23 (s, 3H), 1.88-1.75 (m, 1H), 0.77 (m, 4H) ppm. 1059 370.43 2.42 1060 425.27 0.68 1061 373.05 0.9 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.78 (ddd, J = 7.2, 2.0, 0.8 Hz, 1H), 7.49 (ddt, J = 6.4, 2.8, 1.5 Hz, 3H), 7.19 (d, J = 3.7 Hz, 1H), 7.14-6.97 (m, 1H), 6.37 (dd, J = 7.4, 2.0 Hz, 1H), 4.98 (tt, J = 4.8, 2.5 Hz, 1H), 4.00-3.80 (m, 1H), 2.39 (d, J = 1.0 Hz, 3H), 2.31-2.09 (m, 2H) ppm. 1062 415.37 2.64 1063 457.38 0.71 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.45 (s, 1H), 9.17 (s, 1H), 7.72-7.53 (m, 2H), 7.35-7.16 (m, 2H), 6.84 (s, 1H), 6.39 (s, 1H), 3.90-3.68 (m, 4H), 3.53 (q, J = 7.0 Hz, 3H), 3.30 (s, 2H), 3.05 (d, J = 12.9 Hz, 1H), 2.89 (t, J = 11.9 Hz, 1H), 2.24 (s, 3H), 1.38 (d, J = 6.2 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H) ppm. 1064 454.91 2.44 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.28 (s, 1H), 9.16 (s, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.28-7.23 (m, 1H), 7.02 (s, 1H), 6.56 (d, J = 14.8 Hz, 1H), 6.05 (s, 1H), 4.07 (d, J = 10.5 Hz, 1H), 3.96-3.91 (m, 2H), 3.55-3.40 (m, 5H), 3.29-3.24 (m, 1H), 3.19-3.08 (m, 2H), 2.17 (s, 4H), 2.03-1.98 (m, 1H), 1.65-1.60 (m, 1H) ppm. 1065 400.19 2.05 1066 380.33 0.73 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.05 (s, 1H), 7.94 (dd, J = 11.4, 7.0 Hz, 1H), 7.66 (dd, J = 8.8, 6.4 Hz, 2H), 7.12 (s, 1H), 6.89 (s, 1H), 6.30 (s, 1H), 2.23 (s, 3H) ppm. 1067 443.32 3.57 1068 482.87 2.44 1069 373.99 0.85 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 2.1 Hz, 1H), 7.50-7.42 (m, 1H), 7.34-7.22 (m, 3H), 6.90-6.75 (m, 1H), 6.23 (s, 1H), 4.89 (ddd, J = 7.9, 6.1, 2.1 Hz, 2H), 4.60 (td, J = 6.1, 2.3 Hz, 2H), 4.52 (dd, J = 6.9, 2.3 Hz, 2H), 3.46 (p, J = 7.1 Hz, 1H), 2.39 (s, 3H) ppm. 1070 439.32 0.65 1071 407.16 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.10 (s, 1H), 7.85-7.65 (m, 2H), 7.60 (td, J = 8.4, 6.3 Hz, 1H), 7.18 (tdd, J = 8.4, 2.4, 1.2 Hz, 1H), 6.84-6.58 (m, 2H), 3.81 (s, 4H), 3.22 (s, 4H), 2.19 (s, 4H), 0.84 (d, J = 6.1 Hz, 6H) ppm. 1072 443.15 0.72 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 6.9 Hz, 1H), 7.33-7.28 (m, 1H), 7.25 (s, 1H), 7.02 (s, 1H), 6.83 (ddd, J = 8.6, 6.1, 3.3 Hz, 1H), 5.97 (d, J = 7.9 Hz, 1H), 4.65 (d, J = 10.4 Hz, 2H), 4.22 (s, 2H), 4.09 (d, J = 2.9 Hz, 2H), 3.87 (d, J = 10.5 Hz, 2H), 3.20 (s, 1H), 1.33 (dd, J = 6.5, 1.9 Hz, 6H) ppm. 1073 402.31 0.7 1074 483.4 0.6 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.48 (s, 1H), 9.18 (s, 1H), 7.67-7.57 (m, 2H), 7.37 (s, 1H), 7.25 (tt, J = 9.2, 2.4 Hz, 1H), 6.92 (s, 1H), 6.48 (s, 1H), 3.74 (t, J = 5.0 Hz, 3H), 3.36 (q, J = 5.3 Hz, 3H), 3.12-3.02 (m, 4H), 2.25 (s, 3H), 2.06-1.96 (m, 4H), 1.92-1.81 (m, 2H), 1.79-1.56 (m, 3H) ppm. 1075 371.18 1.69 1076 381.16 2.08 1077 469.35 0.71 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.13 (s, 1H), 8.78 (s, 2H), 7.69-7.53 (m, 2H), 7.26 (tt, J = 9.4, 2.5 Hz, 1H), 6.78 (d, J = 11.3 Hz, 2H), 6.00 (s, 1H), 4.12-3.98 (m, 2H), 3.99-3.85 (m, 2H), 3.80 (dd, J = 12.3, 3.6 Hz, 1H), 3.64 (dd, J = 12.2, 6.2 Hz, 2H), 3.17-3.01 (m, 2H), 2.24 (s, 3H), 2.17-1.89 (m, 6H), 1.89-1.61 (m, 3H) ppm. 1078 472.38 2.36 1079 390.28 3.55 1080 428.12 0.67 1H NMR (300 MHz, Methanol-d4) δ 7.55-7.43 (m, 2H), 7.19 (t, J = 2.2 Hz, 1H), 6.98-6.89 (m, 1H), 6.88 (s, 1H), 6.41 (t, J = 1.7 Hz, 1H), 4.69 (dt, J = 23.9, 6.4 Hz, 4H), 3.62-3.50 (m, 1H), 3.28-3.17 (m, 4H), 2.60-2.46 (m, 4H), 2.30 (s, 3H) ppm. 1081 425.11 0.69 1082 429.33 0.68 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.15 (s, 1H), 7.72-7.60 (m, 2H), 7.25 (tt, J = 9.4, 2.3 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.63 (s, 1H), 6.04 (s, 1H), 3.97-3.86 (m, 2H), 3.81-3.73 (m, 2H), 3.52-3.37 (m, 5H), 3.32-3.19 (m, 2H), 2.19 (s, 3H), 1.23 (d, J = 5.6 Hz, 3H) ppm. 1083 426.31 0.86 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 3.4 Hz, 1H), 9.16 (s, 1H), 7.66-7.52 (m, 2H), 7.27-7.17 (m, 1H), 6.99 (d, J = 12.7 Hz, 1H), 6.54 (s, 1H), 5.91 (s, 1H), 3.86-3.73 (m, 2H), 3.68-3.58 (m, 2H), 3.33-3.28 (m, 1H), 3.27-3.17 (m, 2H), 2.22-2.10 (m, 5H), 2.09-1.96 (m, 2H), 1.68-1.55 (m, 2H) ppm. 1084 471.1 2.12 1085 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.83 (dd, J = 7.3, 1.4 Hz, 1H), 7.75-7.66 (m, 2H), 7.58-7.47 (m, 2H), 7.42-7.34 (m, 1H), 6.96 (d, J = 4.0 Hz, 1H), 6.40 (dd, J = 7.7, 1.5 Hz, 1H), 4.72 (d, J = 6.6 Hz, 4H), 3.75-3.53 (m, 1H), 3.19 (s, 4H), 2.58 (s, 4H), 2.38 (s, 3H) ppm. 1086 384.16 0.66 1H NMR (300 MHz, MeOD + CDCl3) δ 8.48 (s, 1H), 7.80-7.65 (m, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.16 (s, 1H), 6.92 (s, 1H), 6.42 (s, 1H), 3.30 (s, 4H), 2.79 (s, 4H), 2.33 (s, 3H) ppm. 1087 456.3 0.83 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.15 (s, 1H), 7.66-7.55 (m, 2H), 7.24 (tt, J = 6.8, 3.4 Hz, 2H), 6.84 (s, 1H), 6.34 (s, 1H), 3.94 (dd, J = 11.5, 2.7 Hz, 1H), 3.77-3.69 (m, 1H), 3.65 (td, J = 11.4, 2.5 Hz, 1H), 3.59-3.46 (m, 5H), 3.26 (dd, J = 6.9, 1.5 Hz, 2H), 2.71 (s, 1H), 2.69 (td, J = 11.8, 3.4 Hz, 1H), 2.23 (s, 3H), 1.04-0.89 (m, 1H), 0.44 (dt, J = 8.1, 2.9 Hz, 2H), 0.18-0.09 (m, 2H) ppm. 1088 465.06 0.68 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.97 (t, J = 9.5 Hz, 1H), 7.80-7.57 (m, 2H), 7.28 (s, 1H), 6.93 (t, J = 55.7 Hz, 1H), 6.44 (s, 1H), 4.68-4.40 (m, 4H), 3.69-3.51 (m, 4H), 3.50-3.36 (m, 1H), 2.43-2.25 (m, 4H) ppm. 1089 483.06 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.99 (d, J = 2.2 Hz, 1H), 8.02-7.86 (m, 1H), 7.77-7.60 (m, 2H), 7.34 (s, 1H), 6.54 (s, 1H), 4.68-4.40 (m, 4H), 3.63 (s, 4H), 3.46 (d, J = 5.9 Hz, 1H), 2.35 (t, J = 4.9 Hz, 4H) ppm. 1090 465.02 0.69 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.34 (s, 1H), 7.31-7.20 (m, 2H), 6.89-6.75 (m, 1H), 6.51 (d, J = 56.2 Hz, 1H), 6.40 (s, 1H), 4.70 (dt, J = 9.7, 5.2 Hz, 4H), 3.71-3.60 (m, 4H), 3.55 (q, J = 6.4 Hz, 1H), 2.51-2.37 (m, 4H) ppm. 1091 460.11 0.69 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.94-7.76 (m, 1H), 7.73-7.51 (m, 2H), 7.41-7.17 (m, 1H), 6.87-6.63 (m, 2H), 6.43 (s, 1H), 4.73 (d, J = 6.5 Hz, 4H), 3.74-3.50 (m, 1H), 3.46-3.22 (m, 4H), 2.73-2.46 (m, 4H), 2.35 (s, 3H) ppm. 1092 401.08 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.68-7.52 (m, 2H), 7.21 (tt, J = 9.3, 2.4 Hz, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 5.79 (s, 1H), 4.37 (s, 1H), 3.84-3.58 (m, 4H), 2.71 (q, J = 7.4 Hz, 1H), 2.20 (s, 3H), 1.07 (s, 6H) ppm. 1093 400.05 0.67 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.71-7.55 (m, 2H), 7.26 (tt, J = 9.2, 2.4 Hz, 1H), 6.90 (s, 1H), 6.82 (s, 1H), 3.83-3.59 (m, 4H), 3.44-3.32 (m, 4H), 1.97-1.77 (m, 1H), 0.92-0.70 (m, 4H) ppm. 1094 444.2 3.72 1H NMR (300 MHz, CD3OD) δ 8.96 (s, 1H), 7.63-7.40 (m, 3H), 7.06-6.88 (m, 1H), 6.55 (d, J = 2.6 Hz, 1H), 3.77-3.50 (m, 9H), 2.27 (s, 4H), 2.15 (s, 4H) ppm. 1095 434.28 0.81 1H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.11 (d, J = 1.9 Hz, 1H), 7.93 (dd, J = 12.1, 7.3 Hz, 1H), 7.76-7.60 (m, 2H), 7.57-7.44 (m, 1H), 7.33 (s, 1H), 6.68 (s, 1H) ppm. 1096 483.31 0.88 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.09 (s, 1H), 7.97 (dd, J = 11.5, 7.1 Hz, 1H), 7.75-7.60 (m, 2H), 7.38 (s, 1H), 7.32 (s, 1H), 6.81 (t, J = 56.0 Hz, 1H), 6.67 (s, 1H), 2.07-1.93 (m, 1H), 0.86-0.60 (m, 6H) ppm. 1097 435.49 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.14 (s, 1H), 7.66-7.51 (m, 2H), 7.22 (s, 1H), 6.71 (d, J = 12.2 Hz, 2H), 5.82 (s, 1H), 3.89 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.4 Hz, 2H), 3.30-3.25 (m, 1H), 2.19 (s, 3H) ppm. 1098 435.49 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.05 (s, 1H), 7.94 (dd, J = 12.0, 7.1 Hz, 1H), 7.75-7.56 (m, 2H), 6.71 (s, 2H), 5.81 (s, 1H), 3.89 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.3 Hz, 2H), 3.28-3.22 (m, 0H), 2.20 (s, 3H) ppm. 1099 416.4 0.75 1H NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.09 (s, 1H), 7.95 (dd, J = 11.9, 7.0 Hz, 1H), 7.73-7.56 (m, 2H), 7.40 (s, 1H), 7.22 (s, 1H), 6.88 (t, J = 56.4 Hz, 1H), 6.62 (s, 1H) ppm. 1100 501.36 0.95 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.12 (s, 1H), 7.95 (dd, J = 11.8, 7.0 Hz, 1H), 7.73-7.60 (m, 2H), 7.53-7.46 (m, 1H), 7.43 (s, 1H), 6.75 (s, 1H), 2.10-1.95 (m, 1H), 0.84-0.66 (m, 4H) ppm. 1101 416.31 0.85 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.17 (s, 1H), 7.77-7.51 (m, 4H), 7.34 (s, 1H), 7.28-7.14 (m, 1H), 6.68 (s, 1H) ppm. 1102 398.44 0.73 1H NMR (300 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.15 (s, 1H), 7.78-7.66 (m, 2H), 7.60 (td, J = 8.6, 3.9 Hz, 1H), 7.44 (s, 1H), 7.27-7.12 (m, 2H), 7.10-6.67 (m, 1H), 6.62 (s, 1H) ppm. 1103 483.36 0.94 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.18 (s, 1H), 7.78-7.67 (m, 2H), 7.67-7.56 (m, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.27-7.14 (m, 1H), 6.76 (s, 1H), 2.09-1.97 (m, 1H), 0.84-0.61 (m, 4H) ppm. 1104 465.44 0.88 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.16 (s, 1H), 7.80-7.67 (m, 2H), 7.67-7.55 (m, 1H), 7.41 (s, 1H), 7.34 (s, 1H), 7.25-7.15 (m, 1H), 7.13-6.72 (m, 1H), 6.71-6.60 (m, 1H), 2.13-1.90 (m, 1H), 0.87-0.55 (m, 4H) ppm. 1105 400.09 0.7 1H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.25 (s, 1H), 9.01 (s, 1H), 8.72-8.63 (m, 1H), 8.63-8.50 (m, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 6.71 (s, 1H) ppm. 1106 382.09 0.63 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.23 (s, 1H), 9.12-9.00 (m, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.63-8.54 (m, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 7.13-6.71 (m, 1H), 6.65 (s, 1H) ppm. 1107 449.14 0.76 1H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.25 (s, 1H), 9.10 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.60 (s, 1H), 7.40 (s, 2H), 7.11-6.77 (m, 1H), 6.71 (s, 1H), 2.11-1.93 (m, 0H), 0.80-0.70 (m, 4H) ppm. 1108 396.13 0.64 1109 409.99 1.02 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.51-7.22 (m, 9H), 6.80 (t, J = 8.6 Hz, 1H), 6.27 (s, 1H), 4.41 (s, 2H), 2.32 (s, 3H) ppm. 1110 428.49 0.7 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.25 (dd, J = 7.8, 2.0 Hz, 2H), 7.12 (s, 1H), 6.87-6.73 (m, 2H), 6.66 (s, 1H), 6.43 (s, 1H), 4.80-4.61 (m, 4H), 3.40-3.21 (m, 4H), 2.64-2.48 (m, 4H), 2.35 (s, 3H) ppm. 1111 357.29 0.63 1H NMR (300 MHz, MeOD) δ 8.78 (s, 1H), 7.83-7.74 (m, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.19 (s, 1H), 6.91 (s, 1H), 6.40 (s, 1H), 2.49 (s, 3H), 2.29 (s, 3H) ppm. 1112 501.1 0.88 1H NMR (300 MHz, CDCl₃) δ 8.39 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.39-7.27 (m, 1H), 7.23 (s, 1H), 6.88-6.69 (m, 1H), 6.48-6.23 (m, 1H), 4.12-3.90 (m, 2H), 3.71 (d, J = 26.9 Hz, 4H), 3.54-3.26 (m, 3H), 2.83 (dd, J = 22.2, 9.2 Hz, 9H), 2.32 (d, J = 6.4 Hz, 3H), 2.03-1.80 (m, 2H) ppm. 1113 500.2 0.64 1H NMR (300 MHz, CDCl₃) δ 8.36 (s, 1H), 7.71 (s, 1H), 7.40-7.27 (m, 1H), 7.20 (d, J = 5.1 Hz, 1H), 6.75 (s, 1H), 6.32 (d, J = 7.3 Hz, 1H), 3.98 (s, 2H), 3.80-3.26 (m, 9H), 3.12 (d, J = 12.1 Hz, 4H), 2.31 (d, J = 17.6 Hz, 6H), 1.41 (d, J = 6.3 Hz, 3H) ppm. 1114 461.15 0.72 1H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.38 (s, 2H), 7.20 (d, J = 6.0 Hz, 1H), 6.05 (d, J = 8.0 Hz, 1H), 4.03-3.80 (m, 2H), 3.80-3.40 (m, 5H), 3.38-3.26 (m, 2H), 2.82 (s, 1H), 2.51 (s, 1H), 2.37-2.10 (m, 3H), 1.03-0.69 (m, 3H) ppm. 1115 487.11 0.7 1H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.23-7.14 (m, 2H), 6.72 (tt, J = 8.7, 2.3 Hz, 1H), 6.08 (d, J = 7.5 Hz, 1H), 3.98-3.76 (m, 2H), 3.69 (q, J = 7.7 Hz, 2H), 3.41 (dd, J = 8.8, 6.2 Hz, 2H), 3.06 (td, J = 12.8, 6.6 Hz, 3H), 2.61 (dq, J = 15.7, 8.7, 7.9 Hz, 2H), 2.35-2.05 (m, 6H), 1.90 (s, 2H), 1.63 (dq, J = 14.7, 7.5 Hz, 1H) ppm. 1116 487.16 0.72 1H NMR (300 MHz, CDCl₃) δ 8.33 (d, J = 7.2 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 5.8 Hz, 1H), 6.73 (s, 1H), 6.09 (s, 1H), 4.19 (s, 1H), 3.81 (s, 3H), 3.47 (s, 2H), 3.31 (s, 2H), 2.24 (t, J = 4.4 Hz, 6H), 1.46 (s, 1H) ppm. 1117 458.18 0.68 1H NMR (300 MHz, CDCl₃) δ 7.40 (d, J = 6.9 Hz, 1H), 7.24 (s, 1H), 7.20 (dd, J = 7.2, 2.3 Hz, 1H), 5.86 (d, J = 8.0 Hz, 1H), 4.01 (s, 2H), 3.69 (s, 2H), 3.60-3.16 (m, 5H), 2.75 (d, J = 3.8 Hz, 4H) ppm. 1118 459.12 0.71 1H NMR (300 MHz, CDCl₃) δ 8.36 (s, 1H), 7.31 (d, J = 6.9 Hz, 1H), 7.22-7.11 (m, 2H), 6.72 (tt, J = 8.8, 2.4 Hz, 1H), 4.10-3.78 (m, 3H), 3.54 (dd, J = 24.9, 12.1 Hz, 2H), 3.30 (dq, J = 5.9, 4.2 Hz, 2H), 3.19 (dd, J = 13.4, 5.2 Hz, 2H), 3.05-2.76 (m, 3H), 2.38 (dq, J = 7.3, 3.9 Hz, 1H), 1.19 (dq, J = 5.7, 3.8, 3.0 Hz, 2H), 0.89-0.66 (m, 2H) ppm. 1119 447.07 0.71 1H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.37 (s, 2H), 6.71 (dd, J = 12.3, 5.4 Hz, 1H), 4.11-3.79 (m, 4H), 3.62-3.24 (m, 4H), 2.24 (t, J = 8.1 Hz, 3H), 1.15 (t, J = 5.7 Hz, 3H) ppm. 1120 462.09 1.03 1H NMR (300 MHz, CDCl₃) δ 7.38 (s, 1H), 7.12 (s, 2H), 6.57 (s, 1H), 4.14 (s, 1H), 3.62 (d, J = 29.6 Hz, 2H), 3.44-3.15 (m, 3H), 2.90 (s, 1H), 2.58 (s, 1H), 2.21-1.85 (m, 3H), 0.93 (dd, J = 30.1, 9.2 Hz, 8H) ppm. 1121 459.12 0.71 1H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.39 (s, 2H), 7.24 (s, 2H), 7.20 (d, J = 6.3 Hz, 2H), 6.29-5.59 (m, 1H), 3.80 (p, J = 6.2, 5.3 Hz, 4H), 3.49-3.25 (m, 7H), 1.35 (t, J = 9.1 Hz, 2H), 0.83 (t, J = 6.4 Hz, 2H) ppm. 1122 430.1 0.95 1H NMR (300 MHz, CDCl₃) δ 8.33 (s, 1H), 7.38 (d, J = 7.0 Hz, 1H), 7.23-7.14 (m, 2H), 6.78-6.62 (m, 1H), 3.98 (td, J = 7.6, 2.3 Hz, 2H), 3.88-3.75 (m, 2H), 3.71 (td, J = 8.6, 8.0, 5.9 Hz, 1H), 3.56 (dd, J = 13.6, 6.7 Hz, 2H), 3.39 (dd, J = 8.6, 5.7 Hz, 1H), 2.71-2.40 (m, 2H), 2.24 (d, J = 2.9 Hz, 3H), 1.51 (dt, J = 13.6, 7.0 Hz, 1H) ppm. 1123 475.1 0.71 1H NMR (300 MHz, CDCl₃) δ 8.36 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 7.19 (d, J = 2.5 Hz, 1H), 6.86-6.60 (m, 1H), 6.32 (d, J = 7.9 Hz, 1H), 3.28 (tt, J = 5.9, 3.3 Hz, 7H), 2.90 (s, 1H), 1.38 (dd, J = 33.4, 7.4 Hz, 8H) ppm.

Assays for Detecting and Measuring Remyelination Properties of Compounds In Vivo Mouse Cuprizone Assay:

Cuprizone Feeding Protocol:

2 month old female C57BL/6 mice (Stock Number: 000664) were purchased from Jackson Labs and fed for 4-10 months with a 0.2% cuprizone chow (provided by Research Diets, Product # D10020701R, Description AIN-76A Rodent Diet with 0.2% cuprizone) using cuprizone purchased from Sigma (Cat#14690-100G). Chow was provided ad libitum, and refreshed every 4 days to ensure stability of the cuprizone. Mice were maintained on this diet for 4-10 months before initiation of the experiments.

Dosing and PK:

1) 24 hours prior to the start of dosing, 6 to 10 mice were switched from cuprizone chow to normal chow (Picolab rodent diet 20 EXT IRR 5053, irradiated) without added cuprizone. These mice were maintained on normal chow throughout the course of dosing.

2) 6 to 10 mice per group were randomized into new cages such that mice that were housed in one cage during the cuprizone diet were not housed together in one dose group during the study.

3) Mice were dosed with compound in one of two regimens: Regimen A: mice were dosed QD or BID for 14 days via oral gavage. Regimen B: mice were dosed QD or BID for 14 days via IP injection. However, other dosing schedules and/or routes of administration may also be used.

4) On the last day of dosing, dried blood spots were collected at multiple time points following the last dose. Often this was 30 minutes, 2, 6 and 24 hours following the final dose on day 14 via the tail vein.

Perfusion and Sectioning:

1) The day after the last day of dosing, mice were transcardially perfused with 12 ml of PBS (Sigma, P4417) followed by 20 ml of 3.2% paraformaldehyde in PBS (Electron Microscopy Sciences #15714-S). The brains were removed via standard dissection techniques and each was postfixed in 3.2% paraformaldehyde (20 ml) for 24-48 hours at room temperature in sealed scintillation vials.

2) Serial 50 micron sections were collected through the anterior posterior extent of the brain, from just behind the olfactory bulb, through visual cortex using a vibrating microtome, the V-STAR (described in International Publication No. WO 2013/012799 and U.S. Pat. No. 8,967,024 both of which are incorporated herein by reference in their entirety). Sections were collected in phosphate buffered saline (PBS). Vibratome speed was set to 1.1 mm/s and amplitude was set to 0.8 mm.

3) A series of every 24th section was removed for staining yielding 5 sections per brain.

Staining:

1) Tissue sections were stained using an automated system for processing blots (hereinafter the “blotinator”) (described in WO2011/087646 and U.S. Pat. No. 8,337,754 and U.S. Pat. No. 8,679,406 each of which is incorporated herein by reference in its entirety). Brain sections were placed in the blotinator plate and bathed in PBS. The blotinator applied primary antibodies (MOG and MBP together) and Hoechst nuclear stain for 12 hours at room temperature with constant shaking.

The following stains were diluted in blocking buffer (described below):

Hoechst nuclear stain (0.5 mg/ml)(bisBenzimide H 33342 trihydrochloride Sigma #33342).

Myelin basic Protein (MBP) antibody (Abcam Cat # ab7349) was diluted at a 1:750 ratio in blocking buffer).

Myelin Oligodendrocyte Glycoprotein (MOG) (R&D systems Cat # AF2439) was diluted at a 1:250 ratio in blocking buffer.

Antibodies were diluted in blocking buffer, which consisted of 0.3% Triton X-100 (Sigma Cat #234729), 0.02% Sodium Azide (Sigma Cat# S2002) and 8% fetal bovine serum in PBS (Sigma Cat# F2442).

2) The blotinator washed the samples 4 times for 5 minutes each with a wash buffer (0.2% Triton X-100 in PBS).

3) The blotinator applied secondary antibodies diluted in blocking buffer and incubated them for 2 hours with constant shaking.

Alexa 488 donkey anti-rat secondary (Life technologies Cat# A-21208) was diluted at 1:1000 in blocking buffer.

Alexa 568 donkey anti-goat secondary (Life technologies Cat# A-11057) was diluted at 1:1000 in blocking buffer.

Antibodies were also diluted in blocking buffer described above.

4) The samples were then washed 4 times for 5 minutes each with wash buffer (0.2% Triton X-100 in PBS).

5) All 5 sections were mounted on a slide (Fisherbrand Superfrost Plus microscope slide Cat#12-550-15) and coverslip with 50 microliters Fluormount (Sigma cat# F4680-25 ml) in preparation for scanning.

Scanning:

Images were scanned using an Olympus CS120 flourescent scanning microscope. Entire sections were scanned at 10× magnification, with 500 millisecond exposures for the 488 and 568 nanometer fluorescent channels. The Hoechst signal was detected using a 100 millisecond exposure.

In Vivo Myelin Detection Software:

A custom algorithm was developed in house and was used to quantify the amount of new myelin in mice that had been demyelinated with cuprizone and subsequently treated with compounds. Conceptually, the software subtracted a mature myelin marker from a pan-myelin (young and old myelin) marker, and measured the area of the remaining “new” myelin. Myelin oligodendrocyte glycoprotein (“MOG”) is specific to old myelin, while myelin basic protein (“MBP”) is a pan myelin marker, expressed in more immature myelin as well as more mature myelin. This process accounted for the variability inherent in the demyelination process, in which some animals experience more demyelination than others. It more accurately measured myelin generated in response to compound treatment.

The algorithm was written using Definiens Tissue Studio and Definiens Developer XD. There are several steps to the algorithm, each of which are discussed below.

Three channels of information for each sample was loaded. The intensity levels of the three images were summed, and the resulting image was used to determine the “tissue” area. Subsequent analyses was done exclusively on the tissue area.

The MOG channel was loaded and the Definiens “Auto Threshold” function was used to distinguish MOG positive regions from background. Regions of putative white matter with areas <50 pixels were returned to the tissue class. Thus, remaining white matter tracts that resisted demyelination from cuprizone were excluded from subsequent analyses.

The ratio of MBP signal to MOG signal was calculated. This consisted of the mean MBP intensity value divided by the mean MOG intensity value over the entirety of the image. This MBP:MOG ratio was used to normalize the intensity between the MBP and MOG channels. The normalized MOG signal multiplied by 0.5 was subtracted from the MBP signal, creating a new image, “MBP-MOG”. The “Auto Threshold” function was used on the MBP-MOG image, and the ‘new’ myelin consisting of pixels with intensities above the threshold was delineated. Regions of putative new myelin with areas <2 pixels were returned to the tissue class, and the number of pixels positive for “new” myelin was measured.

The algorithm returned the area of the tissue and the MBP positive, MOG negative ‘new’ myelin. Each section was normalized by area relative to its comparable tissue (e.g., the first). Most anterior sections were normalized relative to other first anterior sections. The 5 normalized MBP+/MOG− areas were summed, yielding a total positive area per sample. This yielded a representation of myelin synthesis over the whole extent of the brain, excluding the olfactory bulb and the cerebellum.

Compounds 33, 48, 107, 195, 215, 247, 331, 406, 485, 512, 524 and 691 were tested in the in vivo Mouse Cuprizone assay described above using Regimen A at various doses (milligrams per kilogram or “mpk”) and all had a positive effect (measured as new myelin generated in response to compound treatment compared to control with no added compound). Compound 33 showed a positive effect at 10, 25 and 50 mpk. Compound 48 showed a positive effect at 30, 50 and 100 mpk. Compound 195 showed a positive effect at 60 and 100 mpk. Compound 215 showed a positive effect at 30 and 90 mpk. Compound 406 showed a positive effect at 25 and 50 mpk. Compound 331 showed a positive effect at 20, 30 and 40 mpk. Compound 485 showed a positive effect at 20 and 30 mpk. Compound 512 showed a positive effect at 50 mpk. Compound 524 showed a positive effect at 10, 20 and 30 mpk. Compound 691 showed a positive effect at 8, 10 and 20 mpk. Compound 107 showed a positive effect at 30 and 90 mpk. Compound 247 showed a positive effect at 10, 25 and 50 mpk.

In Vitro Myelination Assay

Compounds were screened for their ability to induce myelination using a primary rat mixed cortical cell culture assay, which contains neurons, oligodendrocyte precursor cells, oligodendrocytes, astrocytes and microglia. The assay quantifies myelination by measuring myelin basic protein (MBP) immunofluorescent positive myelin strands from images taken using a Cellomics Array Scan (model Arrayscan VTI HCS Reader) or a Molecular Devices Image Xpress (model IXM XL) high content imager. The myelin strands were quantitated using a custom created myelin detection software program. Test compounds were dissolved in DMSO to make a 10 mM initial stock solution. Dilutions were made in myelination medium to obtain the final solutions for the assay and were tested in primary rat mixed cortical cells at selected doses.

Primary rat mixed cortical cells were prepared from harvested cerebral cortices from postnatal day 1 (P1) rats (P1 Rat CD® IGS pups) were purchased from Charles River) in Complete Dissociation Medium, wherein the meninges were removed and the cortical tissue chopped with a razor blade into ˜1 mm³ pieces. Tissue from 1-3 pups was collected and placed into 15 ml conical tubes in a total volume of 5 ml of Complete Dissociation Medium. Activated papain (3 ml) was added to each 15 ml conical tube and tissue was incubated at 37° C. for 30 minutes. After the 30 minute incubation, DNase (Sigma D4527; 75 μl of a 1 mg/ml stock) was added to each tube, followed by mechanical trituration using a 2 ml serological pipette and autopipettor to gently dissociate the tissue. Following trituration, larger tissue pieces were allowed to settle by gravity, and the supernatant containing dissociated cells was transferred to a 50 ml conical tube with 4 ml of trypsin inhibitor. Cells were pelleted by centrifugation, resuspended in myelination medium and filtered through a 40 μm filter. Cells were then seeded in 96-well plates (BD Biosciences, Black, PDL-coated, Cat. No. 356640) at 87,500-95,000 cells/well in a final volume of 200 μl of Myelination Medium in the presence or absence of compound and cultured for 14 days in a humidified 37° C. incubator with 5% CO₂. Half the medium was removed and replaced with fresh medium containing 1× compound on days 6 and 10. Using a Biotek automatic plate washer (model Biomek® FXP Laboratory Automation Workstation), cells were fixed with 4% paraformaldehyde on day 14, washed with PBS and blocked in 5% normal goat serum (Vector Laboratories, S-1000) in 0.1% PBS-TritonX-100 (PBST) for 1 hour. Cells were stained with 1:500 anti-MBP (Covance, cat #SMI99) primary antibody in 1% normal goat serum in 0.1% PBST for 2 hours at room temperature followed by 2 washes with PBST. A final incubation in secondary antibody (1:1000, Invitrogen, Alexa-488 anti-mouse IgG2b) and 1:10,000 Hoechst dye in 1% normal goat serum in 0.1% PBST was performed for 2 hours at room temperature. Plates were washed with PBS and then scanned on a Cellomics Array Scan using a 10× objective (25 images per well) or the Image Xpress using a 10× objective (9 image per well). Images were analyzed using Vertex myelin detection software (described below) to quantify total MBP myelin pixels per well. Fold myelin pixels above background at two concentrations (1.0 μM and 10.0 μM) relative to baseline of no added compound are reported below in Table 4. Standard deviation for each compound concentration was calculated using all replicates and using a standard deviation formula commonly used in the art.

One of skill in the art would recognize that for this type of primary neuronal mixed cell assay variability between different assay runs is to be expected even though the protocol is the same for each assay run. For instance, variability may be due to small differences in cell viability, cell density, age of the animals, etc.

Vertex Myelin Detection Software:

The Vertex myelin detection software was used to quantify the amount of myelin wrapping axons in a digital image that was obtained from our in-house microscope. Conceptually, the software identified and traced MBP positive ridge like structures in the image that were indicative of myelinating axons. A confounding factor in the analysis was the large debris fields typically occurring in the images. These fields resulted from the assay conditions required to achieve myelination. Special care was taken to ensure that noise in the image induced by the debris field was appropriately suppressed so that the signal that arose from the myelination could be recovered. The software was written in the Jython programming language and made significant utilization of the Fiji image analysis toolkits (see, Schindelin, J.; Arganda-Carreras, I. & Frise, E. et al., “Fiji: an open-source platform for biological-image analysis”, Nature Methods 9(7): 676-682, 2012). There were several steps to the algorithm, each of which are discussed below.

Initially the image was loaded and converted to a 256-bit grey scale representation. Image contrast was enhanced by performing standard histogram stretching. The saturation parameter for the enhancement was set at 0.35, meaning the upper and lower 3.5% of the distribution of the gray scale values present in the image were removed prior to enhancement. The Frangi[2] vesselness measure, which computes the likelihood of a pixel belonging to a ridge-like structure, was applied to the resulting image (see, Frangi A F, Niessen W J, Vincken K L, Viergever M A “Multiscale vessel enhancement filtering”, Proceedings of Medical Image Computer-Assisted Intervention (MICCAI), Lecture notes in computer science 1496: 130-137, 1998). The Frangi process created a “vessel likeness image” which was then converted to a binary image mask. The threshold of the Frangi measure for conversion to the mask was adjusted so that appropriate regions of the input image were selected. Once the mask was created, morphological closing was applied to remove small holes. Small structures were removed from the mask by deleting regions containing less than 40 connected pixels. The resulting mask overlaps regions of the original image that had a high likelihood of containing myelin strands.

Morphological skeletonization was applied to the binary mask and the resulting image was then converted to a graph data structure. Each node of the graph represented a pixel of the image. Owing to the skeletonizaiton process, each node was connected to at most 4 neighboring pixels. Nodes connected to one other node indicated the end of a myelin strand (“end nodes”); nodes connected to exactly two other nodes indicated a pixel contained in a myelin strand (“myelin node”); while nodes connected to 3 or 4 other nodes indicated regions where myelin strands intersect (“join nodes”). Neighboring ‘myelin nodes’ that were adjacent to the same “join node” were merged into longer strands of myelin. This process was done in a greedy fashion. The longest strand of myelin originating from an “end node” in the graph were identified. If this strand terminated in an end node the strand was extracted from the graph. If the strand terminated at a “join node” then it was joined with one of the other myelin strands adjacent to the same join node. The largest angle between the growing strand and all other strands adjacent to the join node was determined. If this angle was greater or equal to 140 degrees, then the growing strand and the strand that made this large angle were merged into one strand. The two strands that were merged were removed from being adjacent to the “join node”. If the angle was less than 140 degrees, the growing strand was extracted from the graph and removed as being adjacent to the join node. The entire process was repeated until all strands were removed from the graph. Various geometric properties of the strand such as length and maximum curvature were computed from the number of pixels in the strand and the connectivity of the graph.

Before a putative myelin strand was quantified as myelin it was subjected to several quality control measures. The strand needed to be of a sufficient length (at least greater than 40 pixels). To ensure the strand was not overly curved, the ratio of the geometric distance between strand endpoints to the length of the strand needed to be greater than or equal to 0.8. Finally, to ensure the strand was not overly thick, the gray scale gradient at each point on the strand in the directions orthogonal to the strand direction needed to decay sufficiently rapidly. Specifically, the gray scale needed to decrease by 25% from the gray scale value of pixel intersected by the orthogonal line and the putative myelin strand. This decrease needed to occur within 5 pixels. If a strand passes all quality checks it was quantified as myelin.

Reagent and Media Preparation and Animal Source for the In Vitro Myelination Assay

10× Dissociation Media (DM): 10×DM was prepared on a 1 liter scale by combining 900 mM Na2SO4, 300 mM K2SO4, 58 mM MgCl2, 2.5 mM CaCl2, 10 mM HEPES and 20 mL of a phenol red solution (0.5%). The pH was adjusted with 0.1N NaOH by eye until orange-red. The solution was then sterilized by filteration through a 0.2 uM filter (prewashed with 100 ml of deionized sterile water which was discarded prior to filtration of the DM media solution.

10×KyMg Stock: KyMg stock was prepared on a 200 mL scale as follows. To a 250 mL flask was added 190 mL of water, 1 mL of phenol red (Sigma P0290), stock, 1.75 mL of 1N NaOH, 378 mg of kynurenic acid, and 2 mL 500 mM HEPES. The mixture was then sonicated to dissolve the kynurenate and then MgCl2 (4.1 ml of a 4.9 M solution) was added. The pH was adjusted to 7.4 by adding up to 1 ml of 0.1N NaOH and the mixture sterilized by filtration through a prewashed nylon filter (0.2 μm pore).

Complete dissociation medium (DM): 5 mL Ky Mg to 45 mL 1×DM media

Papain Enzyme Solution (Worthington Biochemical, LK003178) A 10 units/mL stock solution was made fresh the day of dissection by adding 1 mL of 10 mM NaOH and Complete Dissociation Medium to one vial of papain (˜100 units) to give a 10 units/mL final concentration. The papain was activated at 37° C. for 10-15 minutes prior to use.

Trypsin Inhibitor Solution: 9.6 mL of Complete Dissociation Medium was added to 100 mg of trypsin inhibitor (type II-O; Sigma T-9253) and the mixture was sonicated. The pH was adjusted to ˜5.75 using 1N NaOH and pH strips. Aliquots (4 mL) were measured out and and stored at −20° C.

DNase I Solution 1 mg/mL): Added 25 mL DMEM/F12 medium (Corning, 10-092-CM) to 20 KU DNAse I (Sigma D4527) and aliquoted into one time use aliquots stored at −20° C.

Myelination Medium: DMEM (Invitrogen, Cat #11960-051) 1:50 B27 (Invitrogen, Cat #17504-044) 1% FBS (HyClone) 2 mM Glutamax (1:100) (Cat # Gibco 25030081)

Pen Strep (1:100) 10,000 units/mL (Cat # Gibco 15140122) PDGF/FGF 0.3 ng/mL each (3 uL per 100 mL; PeproTech, cat #100-13A and cat #100-18B Myelination medium was made fresh the day of use from a stock bottle of DMEM containing pencillin/streptomycin and Glutamax, which was stored at 4° C. for up to one month. On the day of use, 1:50 B27, 1% FBS and 0.3 ng/mL of PDGF and FGF were added to the DMEM containing pencillin/streptomycin and Glutamax.

Other in vitro and in vivo assays and models known in the art may also be used to show induction of remyelination in response to treatment with compounds such as those of the present invention (see, Nalm, F. J. et al., Nature (Letter), published online 20 Apr. 2015, doi:10.1038/nature14335 and Macklin, W. B. et al., Developmental Cell, 32, pp 447-458 (2015))

TABLE 4 Remyelination in vitro data. The activities of the compounds below were determined by testing groups of compounds in different test batches. Compounds with no asterisk were part of one or more in vitro assay testing batches. Compound numbers indicated with an asterisk were all part of the same in vitro assay test batch. Compound numbers with a double asterisk were part of a different in vitro assay test batch. Compound numbers with a # symbol were part of a different in vitro assay batch. Compounds in Table 4 below have between less than 1 fold to greater than 10,000 fold myelin pixels above background at two concentrations (1.0 μM and 10.0 μM) relative to baseline of no added compound. Cmpd No. 10.0 μM 1.0 μM  1 +++ ++++  2 +++ +++  3 ++++ +++  4 − +  5 − ++++  6 ++ +++  7 ++++ ++++  8 + +++  9 +++ ++++  10 − +  11 ++++ ++++  12 + +++  13 − +++  14 − ++++  15 ++ +++  16 ++ +++  17 − +++  18 + ++++  19 + ++  20 +++ ++  21 − ++  22 +++ +++  23 ++ ++  24 +++ ++  25 ++++ ++++  26 − +++  27 +++ ++++  28 − −  29 − −  30 +++ −  31 +++ +++  32 +++ ++++  33 − +++  34 − +++  35 ++ +++  36 − ++++  37 − +++  38 ++ ++  39 − ++++  40 ++ ++++  41 − ++  42 +++ ++  43 +++ +++  44 ++++ ++++  45 +++ ++++  46 + ++++  47 − +++  48 +++ +++  49 ++ −  50 ++++ −  51 +++ +++  52 − ++++  53 − ++  54 +++ ++  55 − +++  56 +++ +++  57 − +++  58 +++ +++  59 +++ +++  60 − ++++  61 − ++++  62 − ++++  63 + ++  64 − ++  65 + ++++  66 ++ ++  67 ++ +  68 ++++ +++  69 ++ ++++  70 ++ −  71 − ++++  72 + ++  73 − +++  74 +++ +++  75 +++ −  76 +++ +++  77 − +++  78 − +++  79 − ++  80 ++++ ++  81 − +  82 +++ ++++  83 ++ −  84 ++ ++++  85 +++ +++  86 +++ +++  87 +++ +++  88 ++++ ++++  89 +++ ++++  90 + +++  91 +++ −  92 +++ ++++  93 +++ ++  94 + +++  95 − ++  96 +++ +++  97 +++ +++  98 − ++  99 − − 100 +++ +++ 101 + ++++ 102 + +++ 103 − +++ 104 +++ ++ 105 + +++ 106 + − 107 ++++ ++++ 108 − ++ 109 − ++ 110 + +++ 111 +++ ++ 112 +++ ++++ 113 − ++++ 114 ++ ++ 115 +++ +++ 116 − − 117 − ++++ 118 ++ +++ 119 ++ +++ 120 − ++++ 121 − +++ 122 ++++ ++ 123 − + 124 − ++++ 125 + ++ 127 + ++++ 128 ++ ++ 129 − − 130 +++ ++++ 131 ++++ ++ 132 + + 133 − ++++ 134 ++ +++ 135 − ++++ 136 ++ + 137 +++ ++++ 138 +++ ++ 139 + +++ 140 + + 141 − +++ 142 +++ ++++ 143 ++++ ++++ 144 − +++ 145 ++ ++ 146 +++ ++++ 147 ++ ++++ 148 +++ +++ 149 ++ ++++ 150 − ++++ 151 − ++ 152 − − 153 ++ +++ 154 +++ +++ 155 +++ +++ 156 − ++++ 157 ++++ ++++ 158 +++ ++ 159 − ++++ 160 − ++++ 161 ++ ++ 162 − − 163 − +++ 164 + + 165 ++ +++ 166 ++ +++ 167 +++ − 168 ++++ ++++ 169 + ++ 170 +++ ++ 171 +++ ++ 172 + ++++ 173 ++ +++ 174 ++ + 175 − ++++ 176 +++ +++ 177 − − 178 + ++++ 179 − +++ 180 − +++ 181 +++ − 182 + ++++ 183 ++ +++ 184 + ++ 185 + +++ 186 ++ ++ 187 − +++ 188 − +++ 189 − +++ 190 − + 191 + − 192 − +++ 193 +++ +++ 194 − ++++ 195 +++ +++ 196 − − 197 +++ +++ 198 ++ +++ 199 +++ +++ 200 +++ +++ 201 − ++++ 202 ++ +++ 203 − +++ 204 − − 205 − +++ 206 +++ +++ 207 − ++ 208 − +++ 209 +++ +++ 210 +++ − 211 +++ ++ 212 − − 213 − +++ 214 ++++ ++ 215 ++ ++ 216 ++ + 217 ++ ++ 218 − +++ 219 + +++ 220 − ++ 221 +++ + 222 + +++ 223 ++ ++ 224 ++ +++ 225 +++ +++ 226 − +++ 227 ++ +++ 228 +++ ++ 229 +++ +++ 230 − ++++ 231 +++ +++ 232 ++ ++ 233 − − 234 +++ + 235 ++ ++ 236 − − 237 +++ ++++ 238 +++ ++++ 239 − ++++ 240 + +++ 241 − − 242 − ++ 243 − +++ 244 ++ + 245 ++ + 246 +++ ++ 247 − +++ 248 + +++ 249 − ++ 250 ++ +++ 251 + +++ 252 ++ ++++ 253 ++ ++++ 254 +++ − 255 +++ +++ 257 − +++ 258 + +++ 259 − ++++ 260 − ++++ 261 ++ ++ 262 +++ ++ 263 +++ ++ 264 ++ ++ 265 +++ +++ 266 +++ ++ 267 − ++ 268 ++++ +++ 269 ++ + 270 +++ +++ 271 − − 272 − ++ 273 − ++++ 274 + ++++ 275 +++ ++ 276 + − 277 +++ ++ 278 + +++ 279 +++ +++ 280 ++ ++++ 281 − + 282 ++ ++ 283 − − 284 + + 285 ++ + 286 +++ +++ 287 +++ +++ 288 ++++ ++++ 289 + ++++ 290 ++++ ++++ 291 + − 292 ++ +++ 293 ++ ++ 294 ++++ ++++ 295 + ++ 296 ++ +++ 297 ++ ++ 298 +++ ++++ 299 ++ +++ 300 − +++ 301 +++ ++++ 302 ++++ ++++ 303 + + 304 − +++ 305 − +++ 306 − − 307 ++ + 308 − ++++ 309 − ++++ 310 +++ ++++ 311 − − 312 + + 313 +++ + 314 ++ ++ 315 +++ +++ 316 − +++ 317 ++ +++ 318 − ++ 319 − + 320 +++ ++ 321 − + 322 + + 323 +++ ++++ 324 ++ + 325 ++ ++ 326 − ++++ 327 +++ +++ 328 +++ +++ 329 ++ + 330 − ++++ 331 ++ + 332 ++ +++ 333 − ++++ 334 ++++ +++ 335 ++ ++++ 336 − + 337 − +++ 338 ++ + 339 ++ +++ 340 − +++ 341 + − 342 ++ ++++ 343 +++ − 344 ++ +++ 345 + ++ 346 ++++ ++++ 347 − − 348 +++ ++++ 349 +++ ++ 350 − − 351 − ++ 352 +++ − 353 +++ ++++ 354 +++ + 355 +++ ++ 356 ++ − 357 + + 358 ND ND 359 − ++++ 360 ++ ++ 361 − +++ 362 − +++ 363 +++ ++++ 364 ++ + 365 − ++ 366 ++++ ++++ 367 +++ +++ 368 + ++ 369 − ++++ 370 +++ ++++ 371 +++ + 372 ++ + 373 +++ +++ 374 +++ +++ 375 ++ ++++ 376 + +++ 377 ++ +++ 378 ++ + 379 +++ ++ 380 ++ +++ 381 +++ + 382 + ++++  383# + ++ 384 +++ +++ 385 +++ +++ 386 ++++ +++ 387 +++ ++ 388 − ++ 389 − ++++ 390 ++ ++ 391 +++ ++++ 392 ++ +++ 393 − +++ 394 − + 395 − ++ 396 ++ ++ 397 +++ ++++ 398 +++ ++++ 399 + ++ 400 − ++++ 401 +++ +++ 402 ++ +++ 403 ++ ++++ 404 +++ +++ 405 ++++ +++ 406 − ++++ 407 − ++++ 408 ++ +++ 409 +++ ++++ 410 − ++ 411 − +++ 412 − ++++ 413 +++ − 414 +++ + 415 − +++ 416 ++ +++ 417 ++++ +++ 418 ++ − 419 − ++ 420 + + 421 +++ +++ 422 +++ − 423 − +++ 424 − +++ 425 +++ + 426 ++++ ++++ 427 +++ +++ 428 ++ + 429 − ++++ 430 − +++ 431 − + 432 + +++ 433 +++ +++ 434 ++++ ++++ 435 +++ +++ 436 +++ ++++ 437 ++ ++ 438 − ++ 439 + + 440 ++ ++ 441 − + 442 ++ ++ 443 − ++++ 444 + − 445 ++ ++ 446 ++++ + 447 ++ ++ 448 + +++ 449 − +++ 450 − − 451 +++ + 452 − ++ 453 ++++ ++ 454 + − 455 ++ − 456 +++ ++++ 457 ++++ ++++ 458 +++ ++++ 459 − ++ 460 ++ +++ 461 − ++++ 462 − +++ 463 − + 464 +++ ++ 465 − +++ 466 − +++ 467 ++ +++ 468 + +++ 469 ++ +++ 470 +++ ++ 471 − + 472 − +++ 473 + +++ 475 ++++ +++ 476 ++ ++ 477 − ++ 478 + + 479 − +++ 480 − ++ 481 +++ +++ 482 +++ ++ 483 − − 484 − − 485 + ++ 486 − +++ 487 + +++ 488 − − 489 ++ ++ 490 ++ ++ 491 − +++ 492 ++++ ++++ 493 − ND 494 ++ +++ 495 − + 496 + +++ 497 − − 498 +++ +++ 499 ++ +++ 500 + +++ 501 − + 502 − + 503 − + 504 ++ ++ 505 − ++ 506 + +++ 507 +++ ++ 508 ++ +++ 509 +++ +++ 510 ++ + 511 +++ +++ 512 +++ +++ 513 +++ +++ 514 +++ ++ 515 + − 516 ++ ++ 517 ++ ++ 518 ++ ++ 519 − +++ 520 − +++ 521 +++ +++ 522 +++ +++ 523 − +++ 524 +++ +++ 525 ++ +++ 526 ++ +++ 527 +++ +++ 528 +++ +++ 529 − + 530 +++ +++ 531 +++ +++ 532 ++ ++ 533 + ++ 534 − + 535 + + 536 +++ +++ 537 − + 538 + + 539 ++ ++ 540 +++ ++ 541 + − 542 ++ ++ 543 + + 544 ++ + 545 ++ ++ 546 ++ + 547 ++ +++ 548 + + 549 ++ + 550 ++ ++ 551 ++ +++ 552 ++ ++ 553 ++ +++ 554 ++ ++ 555 +++ ++ 556 + + 557 − − 558 − ++ 559 ++ +++ 560 +++ ++ 561 ++ +++ 562 + + 563 + − 564 − − 565 − − 566 ++ +++ 567 − − 568 − + 569 ++ + 570 + − 571 + − 572 + − 573 + + 574 ++ +++  575* − ++  576* ++ ++  577* ++ ++  578* ++ +  579** + +  580* + −  581** − ++  582# ++ +  583* ++ ++  584* + ++  585* + ++  586* ++ ++  587* ++ +  588* − ++  589# − ++  590* + ++  591* ++ ++  592** − +  593# − +  594** + +  595** − +  596* ++ ++  597** − +  598** + +  599* ++ ++  600* ++ +  601** − +  602** + +  603* ++ ++  604* − ++  605* ++ ++  606** + +  607* ++ ++  608** + ++  609* +++ +++  610** + +  611* + ++  612* ++ −  613** + ++  614** + +  615* ++ ++  616** − +  617* ++ ++  618* ++ ++  619** + +  620* + ++  621** + ++  622** + +  623* + ++  624# − ++  625** ++ +  626* − ++  627# ++ +  628* + ++  629** − ++  630** + +  631* + +  632* − ++  633* ++ ++  634* ++ ++  635* + ++  636* + +  637* − +++  638* ++ ++  639** + +  640* + ++  641* + ++  642* ++ +  643* − ++  644* ++ +  645* ++ +  646# + ++  647** − +  648* ++ ++  649* − ++  650* + ++  651** + ++  652** − ++  653* − ++  654** + +  655* − ++  656** − +  657* − +  658** − ++  659* ++ ++  660** − −  661* + ++  662* − ++  663** − ++  664* + +  665* + ++  666** + ++  667* + ++  668** + +  669* − ++  670* ++ ++  671* + ++  672** + +  673* +++ ++  674* + +  675** + +  676* − ++  677* − +++  678* + ++  679* + ++  680* ++ ++  681** + ++  682* ++ ++  683** ++ ++  684** ++ ++  685# + ++  686** + +  687** + +  688# − +  689** + +  690* ++ +  691* ++ ++  692* ++ ++  693** − +  694** − ++  695** + +  696* + ++  697* ++ +  698* ++ ++  699# − +  700* − ++  701* − ++  702* ++ ++  703* + ++  704** − ++  705** + ++  706* + +  707* − −  708** − +  709** + +  710# − ++  711* + ++  712* + +  713* ++ ++  714* ++ ++  715** + ++  716* +++ +  717* ++ +  718* +++ ++  719* − +  720** ++ +  721** − ++  722* ++ ++  723** +++ ++  724** + +  725* ++ ++  726* + +  727* − ++  728** − ++  729* ++ −  730* ++ ++  731* − ++  732** + +  733* + +  734** − +  735# + +  736* − ++  737** ++ ++  738# − ++  739* ++ ++  740** ++ ++  741** + ++  742** − ++  743# ++ +  744* − +  745# − ++  746* ++ ++  747# − −  748* − ++  749** ++ ++  750* ++ +  751** − ++  752* + ++  753* +++ ++  754* + ++  755** ++ +  756* ++ +  757* ++ ++  758** ++ ++  759** + +  760** − +  761** − +  762** − −  763* ++ ++  764** + +  765# + ++  766** − +  767** ++ +  768* + −  769** − +  770* ++ ++  771# − ++  772# − +  773* − ++  774* ++ +  775** ++ +  776* − ++  777* ++ +  778* + ++  779** + +  780** + +  781# − +  782# + ++  783** + −  784* ++ ++  785* +++ ++  786** − +  787** ++ +  788** + ++  789** − +  790# ++ ++  791** − ++  792* − ++  793** − +  794** − +  795** + +  796** − ++  797* − +  798** + +  799* − ++  800* ++ ++  801* + +  802* − ++  803* − ++  804** − ++  805* + ++  806** − +  807** + +  808* − ++  809# − +  810# + +  811* ++ +  812* ++ ++  813* + ++  814# + ++  815** ++ +  816** + +  817* ++ ++  818* +++ ++  819* + ++  820* ++ +  821** ++ −  822* − ++  823** ++ ++  824* + ++  825* ++ ++  826* − ++  827* + ++  828# − +  829** − +  830* ++ +++  831* ++ ++  832* ++ ++  833** − +  834** + + 835 ++ +  836** + +  837* ++ +  838# − −  839* − +  840* ++ ++  841# ++ +  842** − +  843** + +  845* + ++  846** + ++  847** + +  848* ++ ++  849** ++ ++  850# − ++  851# ++ +  852** − +  853* ++ +  854* ++ +++  855** + +  856# − ++  857* ++ ++  858# − ++  859** + +  860* + ++  861* − ++  862* ++ +  863* ++ ++  864* ++ ++  865** + +  866** ++ +  867* ++ ++  868** + +  869# + ++  870# + +  871# + +  872# − ++  873# − +  874# − ++  875# − ++  876# ++ ++  877# + +  878# − ++  879# − −  880# − +  881# − ++  882# + +  883# + ++  884# − +  885# − ++  886# + ++  887# ++ ++  888# + +  889# − ++  890# ++ +  891# − +  892# − +  893# − +  894# − ++  895# + ++  896# + +  897# − +  898# − ++  899# + +  900# − +  901# − +  902# − +  903# + ++  904# − −  905# ++ +  906# + ++  907# +++ ++  908# ++ +  909# ++ +  910# ++ +  911# + +  912# + +  913# ++ ++  914# − ++  915# − +  916# − ++  917# − ++  918# − +  919# − ++  920# − ++  921# + ++  922# − +  923# + ++ 924 ND ND  925# − +  926# + ++  927# + ++  928# − ++  929# − ++  930# − ++  931# − ++  932# − +  933# − +  934# − ++  935# ND ++  936# − ++  937# − +  938# − +  939# − +  940# + ++  941# + +  942# − + 943 ND ND  944# − +  945# − +  946# − −  947# − +  948# − ++  949# ++ ++  950# + ++  951# − +  952# + +  953# + +  954# − +  955# + ++  956# − −  957# − ++  958# − ++  959# − +  960# − +  961# + +  962# + + 963 ND ND  964# − −  965# ++ ++  966# − +  967# − ++  968# + +  969# − +  970# − ++  971# + +  972# + −  973# − ++  974# − ++  975# − +  976# ++ +  977# − +  978# + ++  979# − +++  980# + +  981# ++ +  982# − ++  983# + +  984# − ++  985# + +  986# − +  987# − +  988# + ++  989# − −  990# − −  991# + ++  992# + +  993# ++ +  994# + +  995# − ++  996# − +  997# − +++  998# + ++  999# − + 1001# + ++ 1002# ++ +++ 1003# − ++ 1004# + + 1005# − + 1006# + ++ 1007# ++ + 1008# + ++ 1009# + ++ 1010# − + 1011# − ++ 1012# − + 1013# − ++ 1014# + + 1015# − − 1016# + ++ 1017# − ++ 1018# − ++ 1019# ++ + 1020# + ++ 1021# − + 1022# ++ + 1023# ++ + 1024# − ++ 1025# ++ + 1026# + + 1027# − + 1028# + ++ 1029# ++ ++ 1030# + ++ 1031# − ++ 1032# + ++ 1033# − + 1034# − ++ 1035# + + 1036# − − 1037# − ++ 1038# ++ + 1039# − ++ 1040# − ++ 1041# + + 1042# − ++ 1043# − ++ 1044# + + 1045# − + 1046# − + 1047# − + 1048# − ++ 1049# ++ + 1050# − ++ 1051# + ++ 1052# ++ ++ 1053# + ++ 1054# − − 1055# + ++ 1056# − + 1057# − + 1058# ++ ++ 1059# − ++ 1060# − + 1061# ++ ++ 1062# − ++ 1063# − ++ 1064# − ++ 1065# + ++ 1066# − ++ 1067# − + 1068# ++ ++ 1069# + + 1070# − ++ 1071# − ++ 1072# − + 1073# − ++ 1074# − + 1075# − + 1076# − ++ 1077# − + 1078# − + 1079# − ++ 1080# ++ ++ 1081# + + 1082# − ++ 1083# − + 1084# + ++ 1085# ++ ++ 1086# − ++ 1087# + + 1110  + ++++ 1111  − +++

Fold relative to baseline Activity ND not determined ≦1 − >1 to 10x + >10 to 100x ++ >100 to 1000x +++  >1000 to 10,000x ++++

All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the invention. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims. 

We claim:
 1. A compound of formula (I′), or a pharmaceutically acceptable salt thereof,

wherein: X¹ is CH or N; X² is CR^(X2) or N; X³ is CR³ or N; where R³ and R^(X2) are each independently selected from the group consisting of hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, and cyano; provided that X¹, X², and X³ are not simultaneously N, X² and X³ are not simultaneously N and X¹ and X³ are not simultaneously N; L¹ is a bond, —O—, —NR⁵—, —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, or —C(O)—, wherein R⁵ is hydrogen or C₁₋₄alkyl; R¹ is -G¹-L²-R⁶, -G¹-L²-R⁷, G², G³, G⁴, G⁵, G⁶, or -≡-G⁵; G¹ is i) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; or ii) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; L² is a bond, a —C₁₋₃alkylene-, or —C(O)—; R⁶ is a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, and oxo; b) a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and hydroxyl; c) a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L², the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; or d) a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; R⁷ is a) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, and oxo; or b) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, and —C(O)OH; G² is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G² being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₆alkylene-NH₂, —C₁₋₆alkylene-NH(C₁₋₄alkyl), —C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); G³ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L¹, the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G³ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; G⁴ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; G⁵ is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); G⁶ is a monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁶ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, —C(O)OC₁₋₄alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-OH, or G¹⁰, G¹⁰ being a C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen and optionally containing 1 double bond, G¹⁰ being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, and G²⁰, G²⁰ being a C₃₋₆cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G²⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; and R⁴ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R⁴ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —NH(C₁₋₄alkylene-OC₁₋₄alkyl), —NH(C₁₋₄alkylene-OH), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OH), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH.
 2. The compound of claim 1 of formula (I), or a pharmaceutically acceptable salt thereof,

wherein: X¹ and X² are independently CH or N, provided that both X¹ and X² are not simultaneously N; L¹ is a bond, —O—, —NR⁵—, or —NR⁵—C₁₋₄alkylene-, wherein R⁵ is hydrogen or C₁₋₄alkyl; R¹ is -G¹-L²-R⁶, -G¹-L²-R⁷, G², G³, G⁴, or G⁵; G¹ is a 4- to 8-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; L² is a bond or a —C₁₋₃alkylene-; R⁶ is a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, and oxo; or b) a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and hydroxyl; R⁷ is a) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, and oxo; or b) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, and —C(O)OH; G² is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G² being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), and —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); G³ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L, the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G³ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and oxo; G⁴ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and oxo; G⁵ is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen and optionally containing 1 double bond, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, and a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen; R³ is hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, or cyano; and R⁴ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R⁴ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH.
 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is -G¹-L²-R⁶.
 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, and oxo.
 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R⁶ is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, or thietanyl, each being optionally substituted with 1-4 substituents independently selected from C₁₋₄alkyl and oxo.
 6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R⁶ is oxetan-3-yl or 3-methyloxetan-3-yl.
 7. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R⁶ is unsubstituted.
 8. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, and oxo.
 9. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, and hydroxyl.
 10. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R⁶ is pyrazolyl.
 11. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L², the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo.
 12. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo.
 13. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is -G¹-L²-R⁷.
 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R⁷ is a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, and oxo.
 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R⁷ is cyclopropyl, cyclobutyl, or cyclopentyl, each being optionally substituted with hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, or 1-2 halogen.
 16. The compound of any of claims 1, 2 or 13-15, or a pharmaceutically acceptable salt thereof, wherein R⁷ is unsubstituted.
 17. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R⁷ is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, and —C(O)OH.
 18. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein G¹ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo.
 19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein G¹ is piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-1H-pyrrolyl, or 1,2,3,6-tetrahydropyridinyl, G¹ being optionally substituted with 1-4 substituents independently selected from 1 hydroxyl, 1-2 halogen, 1 oxo, and 1-4 C₁₋₄alkyl groups.
 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein the pyrrolidinyl and piperidinyl are optionally substituted with 1-4 substituents independently selected from 1 hydroxyl, 1-2 halogen, and 1 oxo, and the piperazinyl is optionally substituted with oxo.
 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein G¹ is piperazin-1-yl optionally substituted with oxo.
 22. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein G¹ is a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo.
 23. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is 4-(oxetan-3-yl)piperazin-1-yl or 4-(3-methyloxetan-3-yl)piperazin-1-yl.
 24. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is 4-cyclopropylpiperazin-1-yl.
 25. The compound of any of claims 1-22, or a pharmaceutically acceptable salt, wherein L² is a bond.
 26. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L² is a —C₁₋₃alkylene-.
 27. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L² is —C(O)—.
 28. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is G².
 29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein G² is morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, oxazolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2,5-dihydro-1H-pyrrolyl, 1,2,3,6-tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,5-dihydrofuranyl, or 3,6-dihydro-2H-pyranyl, each being optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₆alkyl-NH₂, —C₁₋₆alkyl-NH(C₁₋₄alkyl), —C₁₋₆alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl), and further optionally substituted with 1-3 substituents selected from the group consisting of C₁₋₄alkyl and halogen.
 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein G² is morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, oxazolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2,5-dihydro-1H-pyrrolyl, 1,2,3,6-tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,5-dihydrofuranyl, or 3,6-dihydro-2H-pyranyl, each being optionally substituted with one substituent selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl), and further optionally substituted with 1-3 substituents selected from the group consisting of C₁₋₄alkyl and halogen.
 31. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein G² is piperazin-1-yl optionally substituted with C₁₋₄alkyl.
 32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein G² is 4-methylpiperazin-1-yl.
 33. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is G³.
 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G³ is 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 1-oxa-8-azaspiro[4.5]decanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, where the 2-oxa-5,8-diazaspiro[3.5]nonanyl is optionally substituted with C₁₋₄alkyl and oxo.
 35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G³ is 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-5,8-diazaspiro[3.5]nonanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, the 2-oxa-5,8-diazaspiro[3.5]nonanyl being optionally substituted with C₁₋₄alkyl and oxo.
 36. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is G⁴.
 37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein G⁴ is

each being optionally substituted with one C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, or oxo.
 38. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein G⁴ is

each being optionally substituted with one C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, or oxo.
 39. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is G⁵.
 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein G⁵ is cyclopropyl, cyclobutyl, or cyclopentyl, each optionally substituted as defined in claim
 1. 41. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is G⁶.
 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein G⁶ is thiazole, oxazole, triazole, or pyrazole, each optionally substituted with C₁₋₄alkyl or phenyl.
 43. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is -≡-G⁵.
 44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein G⁵ is cyclopropyl.
 45. The compound of any of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L¹ is a bond.
 46. The compound of any of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L¹ is —O—.
 47. The compound of any of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L¹ is —NR⁵— and R⁵ is hydrogen or C₁₋₄alkyl.
 48. The compound of any of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L¹ is —NR⁵—C₁₋₄alkylene-, wherein R⁵ is hydrogen or C₁₋₄alkyl.
 49. The compound of any of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L¹ is —O—C₁₋₄alkylene-.
 50. The compound of any of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L¹ is —C₁₋₄alkylene-.
 51. The compound of any of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein L¹ is —C(O)—.
 52. The compound of any of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein X¹ is CH and X² is N.
 53. The compound of any of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein X² is CH and X¹ is N.
 54. The compound of any of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein X¹ and X² are each CH.
 55. The compound of any of claim 1 or 3-51, or a pharmaceutically acceptable salt thereof, wherein X¹ is CH, X² is CR^(X2), and X³ is CR³.
 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein X³ is CH.
 57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein X² is C—F.
 58. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein X² is CH.
 59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein X³ is CH.
 60. The compound of any of claim 1 or 3-51, or a pharmaceutically acceptable salt thereof, wherein X¹ is CH, X² is CH, and X³ is N.
 61. The compound of any of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl, pyrazinyl, pyrimidinyl, pyridazinyl, or pyridinyl, and R⁴ is optionally substituted as defined in claim 1 or claim
 2. 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a) phenyl, the phenyl being optionally substituted with one substituent selected from the group consisting of halogen, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, —OC₁₋₄alkyl, C₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH, the phenyl being further optionally substituted with 1-2 substituents independently selected from the group consisting of halogen and C₁₋₄alkyl; b) pyrazinyl, the pyrazinyl being optionally substituted with 1-3 C₁₋₄alkyl groups; c) pyrimidinyl, the pyrimidinyl being optionally substituted with one substituent selected from halogen, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, —OC₁₋₄alkyl, or —C₁₋₄alkylene-OC₁₋₄alkyl, the pyrimidinyl being further optionally substituted with C₁₋₄alkyl; d) pyridazinyl; or e) pyridinyl, the pyridinyl being optionally substituted with one substituent selected from the group consisting of halogen, hydroxyl, C₁₋₄alkyl, and a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the pyridinyl being further optionally substituted with 1-2 substituents selected from halogen and C₁₋₄alkyl.
 63. The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen and C₁₋₄alkyl.
 64. The compound of any of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein R² is C₁₋₄alkyl, C₁₋₄haloalkyl, or C₃₋₆cycloalkyl.
 65. The compound of any of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein R³ is hydrogen.
 66. The compound of claim 1 or claim 2, or claim 87, or a pharmaceutically acceptable salt thereof, selected from the following table: N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-(3-methoxyazetidin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- (3,6-dihydro-2H-pyran-4-yl)pyridin-4-amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-2-yl]cyclobutanol N-[3-chloro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 3-methyl-1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]pyrrolidin-3-ol N-[3-methyl-5-(6-oxa-2-azaspiro[3.3]heptan-2-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- tetrahydrofuran-3-yl-benzene-1,3-diamine 2-cyclopropyl-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-N-(1- phenyl-1,2,4-triazol-3-yl)pyridin-4-amine N-[3,5-di(tetrahydropyran-4-yl)phenyl]-1-phenyl-1,2,4-triazol- 3-amine N-[3-methyl-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine methyl 4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-1-carboxylate N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1- (4-pyridyl)-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- fluorophenyl)-1,2,4-triazol-3-amine N-[3-ethyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine N-[3-[3-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl]-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(6,8-dihydro-5H-imidazo[1,2- a]pyrazin-7-yl)-5-methyl-phenyl]-1,2,4-triazol-3-amine N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[3-(2,5-dimethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-(4-methyl-1-piperidyl)pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-(3-fluoro-1-methyl-pyrrolidin-3- yl)-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-(3-methyl-5-morpholino-phenyl)-1,2,4- triazol-3-amine 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(4-methyl-1,4-diazepan- 1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-[(8aR)-4-isobutyl-3,4,6,7,8,8a-hexahydro-1H- pyrrolo[1,2-a]pyrazin-2-yl]-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 1-(2-methoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(p- tolyl)-1,2,4-triazol-3-amine 1-(3-chloro-5-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1S,4S)-2-(oxetan-3- yl)-2,5-diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3- amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- (3,6-dihydro-2H-pyran-4-yl)pyridin-4-amine 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)azetidin-3- yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine N-(3-methyl-5-pyrrolidin-3-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-[3-[2-(ethoxymethyl)pyrrolidin-1-yl]-5-fluoro-phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 1-(2-chloro-4-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 2-cyclopropyl-6-(4-methyl-1-piperidyl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-4-amine N-(3-methyl-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-(3-fluoro-5-morpholino-phenyl)-1-(2-fluorophenyl)-1,2,4- triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(5- fluoropyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3-[1-[3-(benzenesulfonylmethyl)oxetan-3-yl]-4-piperidyl]- 5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-piperazin-2-yl]methanol N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- methyl-2-pyridyl)-1,2,4-triazol-3-amine 1-(3-chlorophenyl)-N-[3-cyclopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3-fluoro-5-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine (2R)-3-methyl-2-[4-[6-methyl-4-[(1-phenyl-1,2,4-triazol-3- yl)amino]-2-pyridyl]piperazin-2-yl]butan-2-ol N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine [4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-yl]methanol N-[3-methyl-5-(1-methyl-3-piperidyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3,6- dihydro-2H-pyridin-4-yl]phenyl]-1,2,4-triazol-3-amine N-[3-(difluoromethyl)-5-piperazin-1-yl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylsulfanylpyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3-methyl-5-[1-(oxetan-3-yl)azetidin-3-yl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine 2,5-difluoro-4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]benzonitrile 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-(oxetan-3-yl)piperazin-2-one N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyrazin-2- yl-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(p- tolyl)-1,2,4-triazol-3-amine N-[3-methyl-5-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine ethyl 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]acetate N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluoro-5-methyl-phenyl)-1,2,4-triazol-3-amine N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-pyrazin- 2-yl-1,2,4-triazol-3-amine N-[3-[4-(3,3-difluorocyclobutyl)piperazin-1-yl]-5-methyl- phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 1-methyl-4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-one 1-(3,5-difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)- 1,2,4-triazol-3-amine N-[3-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5- yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propane-1,3-diol N-(3-fluoro-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 4-[3-[3-methyl-5-(4-methylpiperazin-1-yl)anilino]-1,2,4- triazol-1-yl]benzonitrile N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-(2-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine N-(3-methyl-5-morpholino-phenyl)-1-(4-pyridyl)-1,2,4-triazol- 3-amine N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-(2-fluoro-4- pyridyl)-1,2,4-triazol-3-amine 1-(3-methoxyphenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-(4-cyclopentylpiperazin-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine N-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]ethanone N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-2-one 1-(3-methoxyphenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(thietan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine N-[3-fluoro-5-(4-methyl-1,4-diazepan-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 2-chloro-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine (3S)-3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 1-(4-fluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 1-[3-(2-ethylpyrrolidin-1-yl)-5-fluoro-phenyl]-N-[3-methyl-5- [4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 2-chloro-N-[1-(3-methoxyphenyl)-1,2,4-triazol-3-yl]-6-(1- piperidyl)pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-piperidyl)phenyl]- 1,2,4-triazol-3-amine N-[3-[3-(dimethylamino)pyrrolidin-1-yl]-5-fluoro-phenyl]-1- (3-fluorophenyl)-1,2,4-triazol-3-amine N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-piperidyl]pyrrolidin-2-one 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]anilino]- 1-piperidyl]ethanone 1-(3,5-difluorophenyl)-N-[3-[3-(methoxymethyl)azetidin-1- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 1-piperidyl]ethanone N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(3,4-dimethylpiperazin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine N-[3-(1-cyclopropyl-4-piperidyl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,6-difluoro-4-pyridyl)-1,2,4-triazol-3-amine 1-(2-fluoro-4-pyridyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 2-[(2S)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-(trifluoromethyl)phenyl]piperazin-2-yl]propan-2- ol N-(3-ethyl-5-piperazin-1-yl-phenyl)-1-pyrazin-2-yl-1,2,4- triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]acetic acid N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl- phenyl]-1-(3-fluorophenyl)-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(2-methyltetrahydrofuran-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine N-[3-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin- 2-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,6-dimethylpyrimidin-4-yl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylsulfanylpyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3-(3,4-dimethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 1-(5-chloro-3-pyridyl)-N-[3-cyclopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 2-chloro-6-morpholino-N-(1-phenyl-1,2,4-triazol-3-yl)pyridin- 4-amine N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1- yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydrofuran-3- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-(2-pyridyl)- 1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-4- oxido-piperazin-4-ium-1-yl]phenyl]-1,2,4-triazol-3-amine 2-fluoro-4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]benzonitrile 1-(3-chlorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-4-carbonitrile methyl 3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-1-carboxylate 1-[4-[3-(difluoromethyl)-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]ethanone 2-chloro-N-[1-(3-methoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 1-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperidine-3-carbonitrile 1-(3-fluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]-1,2,4- triazol-3-amine N-[3-[4-(2-methoxyethyl)-1-piperidyl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- tetrahydropyran-4-yl-pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-methyl-4- piperidyl)phenyl]-1,2,4-triazol-3-amine N-[3-[(8aR)-4-isobutyl-3,4,6,7,8,8a-hexahydro-1H- pyrrolo[1,2-a]pyrazin-2-yl]-5-methyl-phenyl]-1-phenyl-1,2,4- triazol-3-amine N-[3-(4-cyclopropylpiperazin-1-yl)-5- (difluoromethyl)phenyl]-1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3- amine 1-(6-fluoro-2-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-[3-(3-methyl-5-morpholino-anilino)-1,2,4-triazol-1- yl]pyridin-2-ol 2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-4-amine N-[3-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin- 2-yl]-5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine N-(3-fluoro-5-morpholino-phenyl)-1-(3-fluorophenyl)-1,2,4- triazol-3-amine N-(3-methyl-5-piperazin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine N-[3-methyl-5-[1-(oxetan-3-yl)-2,5-dihydropyrrol-3- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]pyrrolidin-2-one 1-(3,5-difluorophenyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 4-[3-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]-1H-pyridin-2-one 1-(3,5-difluorophenyl)-N-[3-(3-methoxypyrrolidin-1-yl)-5- methyl-phenyl]-1,2,4-triazol-3-amine N-(3-morpholino-5-tetrahydrofuran-3-yl-phenyl)-1-phenyl- 1,2,4-triazol-3-amine N-[3-fluoro-5-(1,4-oxazepan-4-yl)phenyl]-1-(3-fluorophenyl)- 1,2,4-triazol-3-amine 1-(4-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine N-(3-bromo-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- pyrrolidin-1-yl-pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(6-oxa-2- azaspiro[3.3]heptan-2-yl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-(4-tetrahydropyran-3-ylpiperazin-1-yl)phenyl]- 1-phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-ethyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine N1-(azetidin-3-yl)-N3-[1-(2,4-difluorophenyl)-1,2,4-triazol-3- yl]-5-fluoro-benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-(4-methyl-1,4-diazepan-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine N-(3-fluoro-5-morpholino-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N1-[1-(3-methoxypropyl)-4-piperidyl]-5-methyl-N3-(1- phenyl-1,2,4-triazol-3-yl)benzene-1,3-diamine 1-(3,4-difluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-fluoro-4-pyridyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-2-(oxetan-3- yl)-2,5-diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3- amine 4-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile 1-[3-[[ethyl(methyl)amino]methyl]-5-fluoro-phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine N3-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-amine N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N3-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-[3-fluoro-1-(oxetan-3- yl)pyrrolidin-3-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 1-piperidyl]ethanone N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine ethyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazine-1-carboxylate N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1,5-dimethyl- N1-(oxetan-3-yl)benzene-1,3-diamine 1-(3,4-difluorophenyl)-N-[3-ethyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydropyran-3- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 7-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin- 3-one 1-(4-fluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- (4-methyl-1-piperidyl)pyridin-4-amine N-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1-(2-ethoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3-fluoro-5-isopropoxy-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3-ethyl-5-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[(3S,4R)-3-fluoro-1-(oxetan-3- yl)-4-piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine; 1- (3,5-difluorophenyl)-N-[3-[(3R,4S)-3-fluoro-1-(oxetan-3-yl)- 4-piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,5-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-morpholino-pyridin-4-amine N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 2-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile N-[3-fluoro-5-(4-methylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 1-cyclopropyl-4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-2-one 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 1-(5-chloro-3-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[(1S,4S)-2-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-5-yl]phenyl]-1-phenyl-1,2,4-triazol- 3-amine 1-(3-chloro-5-fluoro-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-4- piperidyl]phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-6-morpholino-N-(1-phenyl-1,2,4-triazol-3- yl)pyridin-4-amine 1-(2-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- pyridyl)-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-fluorophenyl)-1,2,4-triazol-3-amine 1-(2-fluoro-4-pyridyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 7-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3-one 1-(3,5-difluorophenyl)-N-[3-[4-(1,1-dioxothietan-3- yl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)azetidin-3-yl]phenyl]-1,2,4-triazol-3-amine N-[3-fluoro-5-[1-(oxetan-3-yl)pyrrolidin-3-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(2,6-difluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-[2-(methoxymethyl)phenyl]-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3,5-bis(2,5-dihydrofuran-3-yl)phenyl]-1-phenyl-1,2,4- triazol-3-amine N-[3-[3,3-difluoro-1-(oxetan-3-yl)-4-piperidyl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5-propyl-phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[2,3-dimethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperidin-4-ol N-[3-methyl-5-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy- phenyl]-1-phenyl-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (oxetan-3-yl)benzene-1,3-diamine N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-pyrrolidin-3-ol 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydropyran-4- ylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- (4-methyl-1-piperidyl)pyridin-4-amine 2-cyclopropyl-N-[1-(3,5-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-[(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine N-[3-chloro-5-[4-(methoxymethyl)-1-piperidyl]phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[3-methyl-5-[1-(oxetan-3-yl)-3-piperidyl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine N3-[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]-5-methyl-N1-[1- (oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine N-[3,5-di(tetrahydropyran-4-yl)phenyl]-1-(3-pyridyl)-1,2,4- triazol-3-amine N-(3-morpholino-5-tetrahydropyran-4-yl-phenyl)-1-phenyl- 1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine N-[3-[4-(2-methoxyethyl)piperazin-1-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 1-(6-methoxypyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3-ethyl-5-fluoro-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-(3-methylpiperazin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[3-methyl-5-[1-(oxetan-3-yl)pyrrolidin-3-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-(1-cyclopropyl-4-piperidyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 1-(5-chloro-3-pyridyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-(4- methylpiperazin-1-yl)pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-ethyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6- morpholino-pyridin-4-amine 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]ethanone 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (methylamino)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-fluoro-5-[1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine 1-(4-fluorophenyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-(3-pyridyl)-1,2,4- triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine N-[3-[1-(2,2-difluoroethyl)pyrrolidin-3-yl]-5-methyl-phenyl]- 1-phenyl-1,2,4-triazol-3-amine N-[3-(4-ethylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl-1,2,4- triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- pyridyl)-1,2,4-triazol-3-amine 1-(2,3-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-7- azaspiro[3.5]nonan-7-yl)phenyl]-1,2,4-triazol-3-amine 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]phenyl]- 1,4-diazepan-1-yl]ethanone 3-[3-(3-methyl-5-pyrrolidin-1-yl-anilino)-1,2,4-triazol-1- yl]benzonitrile (3R,4R)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-1-(oxetan-3-yl)piperidin-3-ol; (3S,4S)-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]-1-(oxetan-3-yl)piperidin-3-ol N-[3-(3-aminoazetidin-1-yl)-5-fluoro-phenyl]-1-(2,4- difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3- morpholinopyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluoro-5-isopropoxy-phenyl)-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-ethoxypyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[3-methyl-5-(4-tetrahydropyran-4-ylpiperazin-1-yl)phenyl]- 1-phenyl-1,2,4-triazol-3-amine N-[3-(4-cyclobutylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 1-(5-fluoropyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-[(1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-5- yl]-5-methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(3-methoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[1-(3-methyloxetan-3-yl)-4-piperidyl]phenyl]- 1-phenyl-1,2,4-triazol-3-amine 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]oxazolidin-2-one 2-cyclopropyl-6-[(3R)-3-fluoropyrrolidin-1-yl]-N-(1-phenyl- 1,2,4-triazol-3-yl)pyridin-4-amine N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-(3-pyridyl)- 1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(2,5-dihydrofuran-3-yl)-5- morpholino-phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-[4-(methoxymethyl)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine 1-[3-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]-1-piperidyl]ethanone 1-(3,4-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3- yl)azetidin-3-yl]phenyl]-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (6-methylpyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-1-(oxetan-3- yl)pyrrolidin-3-yl]oxy-phenyl]-1,2,4-triazol-3-amine N-(3-cyclopropyl-5-morpholino-phenyl)-1-phenyl-1,2,4- triazol-3-amine N-[3-(2,6-dimethylmorpholin-4-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine N-(2-fluoro-3-methyl-5-morpholino-phenyl)-1-(2-pyridyl)- 1,2,4-triazol-3-amine N-[3-methyl-5-(4-piperidyl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 5-methyl-N1-[1-(oxetan-3-yl)pyrrolidin-3-yl]-N3-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2-methyl-propane-1,3-diol 1-(2,6-dimethylpyrimidin-4-yl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(oxetan-3-yl)-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3,5-bis(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-phenyl-1,2,4- triazol-3-amine N-[3-methyl-5-(3-piperidyl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 2-[(3R)-1-[3-fluoro-5-[3-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]anilino]-1,2,4-triazol-1-yl]phenyl]pyrrolidin- 3-yl]propan-2-ol 2,6-dimorpholino-N-(1-phenyl-1,2,4-triazol-3-yl)pyridin-4- amine 1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 1-(2,4-difluorophenyl)-N-(3-fluoro-5-morpholino-phenyl)- 1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 1-(3-fluoro-5-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-morpholino-1- piperidyl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[2-(methoxymethyl)morpholin-4- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N-[3-(4-isopropylpiperazin-1-yl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- (1-piperidyl)pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-methyl-3- piperidyl)phenyl]-1,2,4-triazol-3-amine 1-(4,6-difluoro-2-pyridyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3S)-3-fluoropyrrolidin-1-yl]pyridin-4-amine N-[3-methyl-5-(1-methyl-4-piperidyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 5-methyl-N1-[1-(oxetan-3-yl)-4-piperidyl]-N3-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine N-(3-chloro-5-morpholino-phenyl)-1-phenyl-1,2,4-triazol-3- amine N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine N-[3-(4-cyclopropyl-1,4-diazepan-1-yl)-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-5-methyl-phenyl)-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (5-fluoro-3-pyridyl)-1,2,4-triazol-3-amine N-[3-(1-cyclopropyl-3-piperidyl)-5-methyl-phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[3-ethyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-pyrazin-2- yl-1,2,4-triazol-3-amine 5-methyl-N1-[1-(oxetan-3-yl)-4-piperidyl]-N3-[1-(3-pyridyl)- 1,2,4-triazol-3-yl]benzene-1,3-diamine 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(1,4-oxazepan-4- yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methylsulfonyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 2-chloro-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine N-(3-bromo-5-morpholino-phenyl)-1-(3,5-difluorophenyl)- 1,2,4-triazol-3-amine 1-(2,4-difluorophenyl)-N-[3-[3-(dimethylamino)pyrrolidin-1- yl]-5-fluoro-phenyl]-1,2,4-triazol-3-amine N-[3-(4-cyclopropylpiperazin-1-yl)-5- (difluoromethyl)phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(9-methyl-2-oxa-6,9- diazaspiro[3.5]nonan-6-yl)phenyl]-1,2,4-triazol-3-amine 2,2,2-trifluoroethyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate N1-(azetidin-3-yl)-5-fluoro-N3-[1-(3-fluorophenyl)-1,2,4- triazol-3-yl]benzene-1,3-diamine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2,2,2-trifluoro-ethanone N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- [6-(methoxymethyl)pyrimidin-4-yl]-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-dimethoxyphenyl)-1,2,4-triazol-3-yl]- 6-morpholino-pyridin-4-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-ol N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[3-morpholino-5-(trifluoromethyl)phenyl]-1-pyrazin-2-yl- 1,2,4-triazol-3-amine N-[3-(3,3a,4,5,7,7a-hexahydro-2H-furo[2,3-c]pyridin-6-yl)-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-isopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-piperazin-2-one 1-(3-fluorophenyl)-N-[3-methylsulfonyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-phenyl-1,2,4-triazol-3- amine 1-[6-(methoxymethyl)pyrimidin-4-yl]-N-[3-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-methyl-6-(4- methylpiperazin-1-yl)pyridin-4-amine N-[3-morpholino-5-(trifluoromethyl)phenyl]-1-phenyl-1,2,4- triazol-3-amine 2-chloro-6-(4-methylpiperazin-1-yl)-N-(1-phenyl-1,2,4-triazol- 3-yl)pyridin-4-amine tert-butyl 4-[3-ethyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]piperazine-1-carboxylate N-[3-[(3aR,6aR)-1-methyl-2,3,3a,4,6,6a- hexahydropyrrolo[2,3-c]pyrrol-5-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]ethanone N-(3-fluoro-5-morpholino-phenyl)-1-(5-fluoro-3-pyridyl)- 1,2,4-triazol-3-amine N-(3-methyl-5-pyrrolidin-1-yl-phenyl)-1-(p-tolyl)-1,2,4- triazol-3-amine 1-[3-fluoro-5-[2-methoxyethyl(methyl)amino]phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine 1-(3,5-difluorophenyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (6-methoxypyrimidin-4-yl)-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- (1-piperidyl)pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrazol-1-ylazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine N-(3-chloro-5-pyrrolidin-1-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyrimidin- 5-yl-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)pyrrolidin- 3-yl]phenyl]-1,2,4-triazol-3-amine 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1-(4- pyridyl)-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluoro-5-methoxy-phenyl)-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-[3-[[ethyl(methyl)amino]methyl]-5-fluoro-phenyl]-N-[3- methyl-5-(4-methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3- amine N-[3-methyl-5-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy- phenyl]-1-phenyl-1,2,4-triazol-3-amine N-[3-(difluoromethyl)-5-morpholino-phenyl]-1-phenyl-1,2,4- triazol-3-amine N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-2,6- dimorpholino-pyridin-4-amine N-(3-fluoro-5-morpholino-phenyl)-1-(4-fluorophenyl)-1,2,4- triazol-3-amine 1-(3-fluoro-5-methoxy-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- propyl-phenyl]-1,2,4-triazol-3-amine 1-(3-chlorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl]- 1-phenyl-1,2,4-triazol-3-amine N-[3-methyl-5-(4-methylpiperazin-1-yl)phenyl]-1-pyridazin-4- yl-1,2,4-triazol-3-amine 1-(3-chloro-5-fluoro-phenyl)-N-[3-cyclopropyl-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3-yl)amino]anilino]- 1-piperidyl]ethanone 1-(2-fluoro-4-pyridyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine N-[3-methyl-5-(oxetan-3-yl)phenyl]-1-(2-pyridyl)-1,2,4- triazol-3-amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- morpholino-pyridin-4-amine 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6- tetrahydropyran-4-yl-pyridin-4-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3- piperidyl]phenyl]-1,2,4-triazol-3-amine 1-(4-fluorophenyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]-1,2,4- triazol-3-amine N-[3-methyl-5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]phenyl]-1- phenyl-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-methyl-5-[1-(oxetan-3-yl)-3- piperidyl]phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-(4-methylpiperazin-1-yl)-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,4,5-trifluorophenyl)-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(o- tolyl)-1,2,4-triazol-3-amine 1-(3-fluoro-5-isopropoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 1-(2,5-difluorophenyl)-N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- methylpyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3-methyl-5-(2,4,5-trimethylpiperazin-1-yl)phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-(6- methylpyrazin-2-yl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine methyl 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazine-1-carboxylate N-[3-methyl-5-[(3R,5S)-3,4,5-trimethylpiperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3-fluoro-5-methyl-phenyl)-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-(3-chloro-5-morpholino-phenyl)-1-(3,5-difluorophenyl)- 1,2,4-triazol-3-amine 1-(5-fluoro-3-pyridyl)-N-(3-methyl-5-morpholino-phenyl)- 1,2,4-triazol-3-amine 1-(2-chlorophenyl)-N-[3-methyl-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-piperidyl)phenyl]- 1,2,4-triazol-3-amine 2-(4-fluoro-1-piperidyl)-6-methyl-N-(1-phenyl-1,2,4-triazol-3- yl)pyridin-4-amine N-[3-methyl-5-[4-[(3-methyloxetan-3-yl)methyl]piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methoxyphenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-4- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-(4-tetrahydrofuran-3-ylpiperazin-1-yl)phenyl]- 1-phenyl-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperidin-3-ol N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methylsulfanylphenyl)-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-(3-fluoro-5-morpholino-phenyl)- 1,2,4-triazol-3-amine N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-1-[4- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 3-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-piperidyl]cyclobutanecarboxylic acid 1-[3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]pyrrolidin-1-yl]ethanone 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-7- azaspiro[3,4]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 1-(2,3-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(2-chlorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin- 1-yl]phenyl]-1,2,4-triazol-3-amine 1-(5-fluoro-3-pyridyl)-N-[3-methyl-5-(oxetan-3-yl)phenyl]- 1,2,4-triazol-3-amine N1-cyclopropyl-N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-5-methyl-benzene-1,3-diamine 1-[3-[3-methyl-5-[(1-pyrimidin-4-yl-1,2,4-triazol-3- yl)amino]phenyl]-1-piperidyl]ethanone 1-(2,4-difluorophenyl)-N-[3-fluoro-5-(4-methylpiperazin-1- yl)phenyl]-1,2,4-triazol-3-amine N-(2-fluoro-3-methyl-5-morpholino-phenyl)-1-(3-pyridyl)- 1,2,4-triazol-3-amine N-(3-fluoro-5-pyrrolidin-3-yl-phenyl)-1-phenyl-1,2,4-triazol- 3-amine N-[3-[4-(3,3-difluorocyclobutyl)piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2-methylpyrimidin-4-yl)-1,2,4-triazol-3-amine N-[3-[4-(2-fluorophenyl)piperazin-1-yl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-(3-morpholino-5-tetrahydrofuran-3- yl-phenyl)-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-(4-fluoro-1- piperidyl)-6-methyl-pyridin-4-amine cyclopropyl-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]methanone 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-6-[(3S)-3-fluoropyrrolidin-1-yl]-N-(1-phenyl- 1,2,4-triazol-3-yl)pyridin-4-amine 2-methyl-1-[4-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]propan-2-ol N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (3-fluorophenyl)-1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- methylsulfanylphenyl)-1,2,4-triazol-3-amine N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine N-[3-(2,5-dihydrofuran-3-yl)-5-morpholino-phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[3-(1-cyclopropyl-3-piperidyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 1-[3-fluoro-5-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]-N-[3- methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol- 3-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1-(2,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[2,3-dimethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[2-methoxy-3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)pyrrolidin-3-yl]benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3R)-1-(oxetan-3- yl)pyrrolidin-3-yl]phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-(2,2,3,3,5,5,6,6-octadeuterio-4-methyl- piperazin-1-yl)phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-morpholino-5- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 1-(2-fluoro-5-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 2-chloro-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methylpiperazin-1-yl)pyridin-4-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[4- (trifluoromethoxy)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[(1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]phenyl]-1-phenyl-1,2,4-triazol- 3-amine [1-[3-fluoro-5-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]anilino]-1,2,4-triazol-1-yl]phenyl]pyrrolidin-3-yl]methanol N-[3-[4-(methoxymethyl)-1-piperidyl]-5-methyl-phenyl]-1- phenyl-1,2,4-triazol-3-amine N-[3-(4-cyclopropylpiperazin-1-yl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine N-[3-methyl-5-[1-[(3-methyloxetan-3-yl)methyl]-4- piperidyl]phenyl]-1-phenyl-1,2,4-triazol-3-amine N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,3,5-trifluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]-1- phenyl-1,2,4-triazol-3-amine (3R)-3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-1-(oxetan-3-yl)pyrrolidin-3-ol 1-(6-chloro-2-pyridyl)-N-(3-methyl-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine N-[3-ethyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]- 1-pyrazin-2-yl-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(2-methyltetrahydrofuran-2-yl)methyl]benzene-1,3-diamine 1-[3-fluoro-5-[(2R)-2-(methoxymethyl)pyrrolidin-1- yl]phenyl]-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3S)-3-fluoropyrrolidin-1-yl]pyridin-4-amine [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]methanol N-[3-cyclopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- [3-fluoro-5-(3-methoxyazetidin-1-yl)phenyl]-1,2,4-triazol-3- amine 1-[2-(azepan-1-yl)-4-pyridyl]-N-[3-methyl-5-(4- methylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (2-tetrahydrofuran-2-ylethyl)benzene-1,3-diamine 1-(2,4-difluorophenyl)-N-(3-fluoro-5-pyrrolidin-1-yl-phenyl)- 1,2,4-triazol-3-amine 2-cyclopropyl-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6- [(3R)-3-fluoropyrrolidin-1-yl]pyridin-4-amine 3-[3-[3-methyl-5-(4-methylpiperazin-1-yl)anilino]-1,2,4- triazol-1-yl]benzonitrile N-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]pyrrolidin-3-yl]-N-methyl-acetamide N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine 4-methyl-6-(3-morpholinoazetidin-1-yl)-N-(1-phenyl-1,2,4- triazol-3-yl)pyridin-2-amine 4-methyl-6-(3-morpholinoazetidin-1-yl)-N-[1-(2-pyridyl)- 1,2,4-triazol-3-yl]pyridin-2-amine N-[1-(2-fluoro-4-pyridyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine [3-acetoxy-2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-1-yl]-2-methyl-propyl] acetate 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(oxetan-3- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-[4-(oxetan-3-yl)-1-piperidyl]-5-(trifluoromethyl)phenyl]- 1-pyrazin-2-yl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-6- azaspiro[3.3]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-2-methyl-propanoic acid 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrrolidin-1- ylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-isopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine N-[3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[4-fluoro-1-(oxetan-3-yl)-4- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(oxetan-3-yl)piperidin-4-ol 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]oxazolidin-2-one 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-isopropyl-azetidin-3-ol 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]propan-2-ol N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(3- methoxycyclobutyl)-5-methyl-benzene-1,3-diamine N-[3-methyl-5-[4-(oxetan-3-yl)-1-piperidyl]phenyl]-1-pyrazin- 2-yl-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1- piperidyl]phenyl]-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-isopropyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-(difluoromethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 4-(difluoromethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1- phenyl-1,2,4-triazol-3-yl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)phenyl]-1,2,4-triazol-3-amine N-[3-(3,3a,4,6,7,7a-hexahydro-2H-furo[3,2-c]pyridin-5-yl)-5- methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- piperazin-1-yl-pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(3S)- tetrahydrofuran-3-yl]piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(3R)- tetrahydrofuran-3-yl]piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(2- pyridyl)-1,2,4-triazol-3-yl]pyridin-2-amine tert-butyl 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-4-methyl-2-pyridyl]piperazine-1-carboxylate [2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-3-hydroxy-2-methyl-propyl]acetate N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine N-[3-isopropyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- morpholinoazetidin-1-yl)pyridin-2-amine N-[3-cyclopropyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-8- azaspiro[3.5]nonan-8-yl)phenyl]-1,2,4-triazol-3-amine 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]pyrrolidin-2-one 1-(3,5-difluorophenyl)-N-[3-methyl-5-(9-oxa-6- azaspiro[3.5]nonan-6-yl)phenyl]-1,2,4-triazol-3-amine N-[3-ethyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-pyrimidin- 5-yl-1,2,4-triazol-3-amine N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1-phenyl-1,2,4-triazol-3- yl)-4-(trifluoromethyl)pyridin-2-amine 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(2-pyridyl)-1,2,4- triazol-3-yl]-4-(trifluoromethyl)pyridin-2-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine N-[3-tert-butyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrimidin-5-yl-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-methyl-azetidin-3-ol 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (trifluoromethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-ethyl-azetidin-3-ol 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- (trifluoromethyl)-2-pyridyl]-N-ethyl-piperazine-1- carboxamide 1-[4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- (trifluoromethyl)-2-pyridyl]piperazin-1-yl]ethanone N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-piperazin-1-yl- 4-(trifluoromethyl)pyridin-2-amine tert-butyl 4-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-4-(trifluoromethyl)-2-pyridyl]piperazine-1- carboxylate 1-(2,5-difluorophenyl)-N-(3-methyl-5-piperazin-1-yl-phenyl)- 1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-1-yl]-5- propyl-phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- morpholino-pyridin-2-amine 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin- 6-one N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(4- tetrahydrofuran-3-ylpiperazin-1-yl)pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[3- (oxetan-3-yl)azetidin-1-yl]pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- tetrahydrofuran-3-ylpiperazin-1-yl)-4-(trifluoromethyl)pyridin- 2-amine ethyl 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 4-methyl-2-pyridyl]piperidine-4-carboxylate N-[3-(3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin- 8-yl)-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-[4-(oxetan-3- yl)piperazin-1-yl]-6-(trifluoromethyl)pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3-fluoro-1- piperidyl)-4-methyl-pyridin-2-amine 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]-4-methyl-piperidin-4-ol N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(7- oxa-2-azaspiro[3.4]octan-2-yl)pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(3- oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-amine 2-[1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]azetidin-3-yl]propan-2-ol N-[3,5-bis(4-tert-butylpiperazin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine N-[3,5-bis[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine N-[3-methyl-5-(2-morpholinoethoxy)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1- pyrazin-2-yl-1,2,4-triazol-3-yl)pyridin-2-amine 1-(3,4-difluorophenyl)-N-[3-ethyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 4-(1,1-difluoroethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- (3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-morpholino-methanone N-[3-methyl-5-[[4-(oxetan-3-yl)piperazin-1- yl]methyl]phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N-[(1S)-2-methoxy-1-methyl-ethyl]azetidine- 3-carboxamide N-[3-methyl-5-[4-(3-methyloxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(4-oxa-7- azaspiro[2.5]octan-7-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1-(3,5-difluorophenyl)-N-[2-fluoro-3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 5-methyl-N1-(5-methylthiazol-2-yl)-N3-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]-morpholino-methanone 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-isopropoxy-2-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 3-[4-(oxetan-3-yl)piperazin-1-yl]-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]benzonitrile 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2- morpholinoethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[4-(oxetan-3- yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine 1-(3-chloro-4-fluoro-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methoxy-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 4-methyl-N2-tetrahydrofuran-3-yl-N6-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridine-2,6- diamine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3- morpholinoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-[3-(2,2-dimethylmorpholin-4- yl)azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine (5S)-5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one N1-(1-ethyl-1,2,4-triazol-3-yl)-5-methyl-N3-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1-methylpyrazol-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 1-(4-fluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-4-carbonitrile 3-morpholino-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]benzonitrile N-[3-methyl-5-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]phenyl]-1- (2-pyridyl)-1,2,4-triazol-3-amine 4-methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine (5S)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3,5-dimethyl-oxazolidin-2-one N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-fluoro-4-(3- morpholinoazetidin-1-yl)pyridin-2-amine 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3,5-dimethyl-oxazolidin-2-one N6-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-N2- tetrahydrofuran-3-yl-pyridine-2,6-diamine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(3-methyloxetan-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-methyl-4-(3- morpholinoazetidin-1-yl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-[3-(4-fluoro-1-piperidyl)azetidin- 1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[3-[(2R,6S)-2,6- dimethylmorpholin-4-yl]azetidin-1-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[1-(oxetan-3-yl)-3- piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 1-(4-fluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 1-(3-fluoro-4-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-(methoxymethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 1-[4-[3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenoxy]-1-piperidyl]ethanone 1-(3,4-difluorophenyl)-N-[3-methyl-5-(tetrahydropyran-4- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[5-methyl-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[[4-(oxetan-3- yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[(3S)-1-(oxetan-3-yl)- 3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(1-piperidyl)azetidin- 1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-(3-methyl-5-tetrahydropyran-3- yloxy-phenyl)-1,2,4-triazol-3-amine N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-6-(3- morpholinoazetidin-1-yl)-4-(trifluoromethyl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1,4- diazepan-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-(3-methyl-5-tetrahydropyran-3- yloxy-phenyl)-1,2,4-triazol-3-amine N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4- methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine N-[3-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-phenyl]-1- (3,4-difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-isopropoxy-2-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine 5-methyl-N3-(1-phenyl-1,2,4-triazol-3-yl)-N1-thiazol-2-yl- benzene-1,3-diamine N-[3-methyl-5-(2-pyrazol-1-ylethoxy)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-[4-(methoxymethyl)-1-piperidyl]pyridin-2- amine 1-(3,5-difluoro-4-methoxy-phenyl)-N-[3-methyl-5-[4-(oxetan- 3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(4-fluoro-3-methyl-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(tetrahydrofuran-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (3-morpholinocyclobutyl)benzene-1,3-diamine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- methylpiperazin-1-yl)-4-[4-(oxetan-3-yl)piperazin-1- yl]pyridin-2-amine N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(5-oxa-2- azabicyclo[4.1.0]heptan-2-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-isopropoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(4- ethylpiperazin-1-yl)-4-(trifluoromethyl)pyridin-2-amine (5R)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-5-methyl-oxazolidin-2-one 3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile N-[3,5-bis(4-methylpiperazin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5-methyl-oxazolidin-2-one 1-(3,4-difluorophenyl)-N-[3-methyl-5-[3-(1,4-oxazepan-4- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 6-chloro-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-(3- morpholinoazetidin-1-yl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-[3-(1,1-dioxo-1,4-thiazinan-4- yl)azetidin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N-[3-methoxy-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[6-methyl-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-N- methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-4- carboxamide 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[(3R)-1-(oxetan-3-yl)- 3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 3-morpholino-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]benzonitrile 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-2-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 3-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile N3-(1-isopropylpyrazol-3-yl)-5-methyl-N1-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(3R)-3- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine N-[3-methyl-5-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-[(3R)- tetrahydrofuran-3-yl]piperazin-1-yl]-4- (trifluoromethyl)pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- [(3R)-tetrahydrofuran-3-yl]piperazin-1-yl]pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-morpholino-4- (trifluoromethyl)pyridin-2-amine methyl 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6- morpholino-pyridine-4-carboxylate 5-methyl-N3-(1-methyl-1,2,4-triazol-3-yl)-N1-(1-phenyl- 1,2,4-triazol-3-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3-methyloxetan-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4- (oxetan-3-yl)piperazin-1-yl]benzonitrile (5S)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-5-methyl-oxazolidin-2-one 4-(difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 5-methyl-N1,N3-bis(1-phenyl-1,2,4-triazol-3-yl)benzene-1,3- diamine (5R)-5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methyl-3- morpholino-azetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-[1-(3-pyridyl)-1,2,4- triazol-3-yl]-4-(trifluoromethyl)pyridin-2-amine 4-(1,1-difluoroethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol- 3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-fluoro-N1- (oxetan-3-yl)benzene-1,3-diamine 4-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile N-[3-(2,6-diazaspiro[3.3]heptan-2-yl)-2-fluoro-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine N6-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4- methyl-N2-tetrahydrofuran-3-yl-pyridine-2,6-diamine [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]-morpholino-methanone 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)phenyl]-1,2,4-triazol-3-amine 1-[3-(difluoromethyl)phenyl]-N-[3-methoxy-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine 1-(4-fluorophenyl)-N-[3-methyl-5-[4-(3-methyloxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(2R)-2- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1-(3,5-difluorophenyl)-N-[2,5-dimethyl-3-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2-pyrazol-1- ylethoxy)phenyl]-1,2,4-triazol-3-amine 5-methyl-N3-(5-methyl-1H-pyrazol-3-yl)-N1-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[(3S)-1-(oxetan-3-yl)- 3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(3-morpholinoazetidin-1-yl)-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 6-(4-tert-butylpiperazin-1-yl)-N-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-4-methyl-pyridin-2-amine 1-(3,5-difluorophenyl)-N-(3-methyl-5-tetrahydrofuran-3- yloxy-phenyl)-1,2,4-triazol-3-amine N-[3-methyl-5-(3-morpholinoazetidin-1-yl)phenyl]-1-phenyl- 1,2,4-triazol-3-amine 5-chloro-N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1- (oxetan-3-yl)benzene-1,3-diamine N-[3-[(3,3-difluorocyclobutyl)methoxy]-5-methyl-phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-2-carbonitrile 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-methyl-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine N-[3-(4-tert-butylpiperazin-1-yl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 1-(4-methoxyphenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N,N-dimethyl-azetidine-3-carboxamide 6-[4-(oxetan-3-yl)piperazin-1-yl]-N-(1-pyrazin-2-yl-1,2,4- triazol-3-yl)-4-(trifluoromethyl)pyridin-2-amine [2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]-4-pyridyl]methanol 1-(3,4-difluorophenyl)-N-[3-methyl-5-[(1-methylpyrazol-3- yl)methoxy]phenyl]-1,2,4-triazol-3-amine 1-(3-chloro-4-methyl-phenyl)-N-[3-ethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 4-(difluoromethyl)-6-(3-morpholinoazetidin-1-yl)-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin- 1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3-fluorophenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)phenyl]-1,2,4-triazol-3-amine N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(2,5-dioxa-8-azaspiro[3.5]nonan- 8-yl)-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-(4-morpholino-1- piperidyl)phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4,6-bis[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)phenyl]-1,2,4-triazol-3-amine N-[1-(4-fluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(oxetan-3- yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2-amine 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(methoxymethyl)-1-piperidyl]pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(2S)-2- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(4- methylpiperazin-1-yl)pyridin-2-amine 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-6-(3-morpholinoazetidin-1-yl)pyridin-2-amine 6-chloro-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 3-[3-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile 1-(3-fluoro-4-methoxy-phenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-[3-(difluoromethyl)phenyl]-N-[3-ethyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 3-[[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1,5-dimethyl- N1-(2-morpholinoethyl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[4- [(3S)-tetrahydrofuran-3-yl]piperazin-1-yl]pyridin-2-amine 5-methyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-(4- piperidyl)pyridin-2-amine N-[3-[4-(3,3-difluoroazetidin-1-yl)-1-piperidyl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[4-[3- (dimethylamino)propyl]piperazin-1-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[[(3R)-1-(oxetan-3-yl)- 3-piperidyl]oxy]phenyl]-1,2,4-triazol-3-amine N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4-methyl- 6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2R)-2-methyl-4- (oxetan-3-yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2R)-4-(oxetan-3- yl)morpholin-2-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3- morpholinocyclobutoxy)phenyl]-1,2,4-triazol-3-amine N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-pyrazin- 2-yl-1,2,4-triazol-3-amine 1-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[3-methoxy-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]piperidin-3-ol 4-(difluoromethyl)-N-[1-[3-(difluoromethyl)phenyl]-1,2,4- triazol-3-yl]-6-(3-morpholinoazetidin-1-yl)pyridin-2-amine 1-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[3-methyl-5-[4- (oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[1-(4-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- methoxy-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 3-[3-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-[4-(oxetan-3- yl)piperazin-1-yl]-6-(trifluoromethyl)pyridin-4-amine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(3- fluoro-4-methyl-phenyl)-1,2,4-triazol-3-amine 4-[3-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,2,4- triazol-1-yl]benzonitrile 3-morpholino-5-[[1-(3-pyridyl)-1,2,4-triazol-3- yl]amino]benzonitrile N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3-methoxy-1- piperidyl)-4-methyl-pyridin-2-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-tetrahydrofuran-3-yl-benzene-1,3-diamine N-[3-(3-fluoroazetidin-1-yl)-5-methyl-phenyl]-1-[3-fluoro-5- (2-methoxyethylamino)phenyl]-1,2,4-triazol-3-amine 1-(3-chloro-4-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4-methyl- 6-(3-morpholinoazetidin-1-yl)pyridin-2-amine N-[3-(2-cyclopropylethynyl)-5-methyl-phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-morpholino-4- (trifluoromethyl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3,3,4- trimethylpiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(4-methylpiperazin- 1-yl)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]-pyrrolidin-1-yl-methanone N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-(3,6-dihydro- 2H-pyran-4-yl)-4-methyl-pyridin-2-amine 3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- fluoro-phenyl]oxetan-3-ol 1-(2-fluoro-4-pyridyl)-N-[3-methyl-5-[4-(oxetan-3-yl)-1,4- diazepan-1-yl]phenyl]-1,2,4-triazol-3-amine 4-(difluoromethyl)-N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]-6-(2-oxa-8-azaspiro[3.5]nonan-8-yl)pyridin-2-amine 1-(3,4-difluorophenyl)-N-(3-methyl-5-tetrahydrofuran-3- yloxy-phenyl)-1,2,4-triazol-3-amine 1-(3-fluoro-4-methyl-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(4-fluoro-3-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3-fluoro-4-methoxy-phenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluoro-4-methoxy-phenyl)-N-[3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-fluoro-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3,4- difluorophenyl)-1,2,4-triazol-3-amine N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(2- pyridyl)-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[3- (methoxymethyl)-1-piperidyl]-4-methyl-pyridin-2-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-[(3S)- tetrahydrofuran-3-yl]piperazin-1-yl]-4- (trifluoromethyl)pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 2-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]amino]-N- methyl-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridine-4- carboxamide 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 2-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]amino]ethanol N1-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (3-morpholinocyclobutyl)benzene-1,3-diamine 3-[[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]amino]-5-[4-(oxetan- 3-yl)piperazin-1-yl]benzonitrile 1-[3-(difluoromethyl)phenyl]-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-(difluoromethyl)-6-[4-(methoxymethyl)-1-piperidyl]-N-[1- [3-(trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine (5R)-5-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]-3,5-dimethyl-oxazolidin-2-one N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (3-morpholinocyclobutyl)benzene-1,3-diamine N-[3-(2-cyclopropylethynyl)-5-methyl-phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine N3-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (3-morpholinocyclobutyl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-[(3S)-3- methylmorpholin-4-yl]azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6-[1- (oxetan-3-yl)-4-piperidyl]pyridin-2-amine N-[3-ethyl-5-[4-(3-methyloxetan-3-yl)piperazin-1-yl]phenyl]- 1-(4-fluorophenyl)-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-fluoro-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-(difluoromethyl)-5-(3-morpholinoazetidin-1-yl)phenyl]- 1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenoxy]-1-piperidyl]ethanone 4-(difluoromethyl)-N-[1-(4-fluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-(trifluoromethyl)pyridin-2- amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(1,4-oxazepan-4- yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[4-[2- (dimethylamino)ethyl]piperazin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-tetrahydropyran-4-yl-benzene-1,3-diamine N-[3-isopropoxy-2-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2- morpholinoethoxy)phenyl]-1,2,4-triazol-3-amine N-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenoxy]cyclobutyl]acetamide 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-oxa-8- azaspiro[4.5]decan-8-yl)phenyl]-1,2,4-triazol-3-amine [1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]-3-piperidyl]methanol 1-(3,5-difluorophenyl)-N-[3-[3-(2- methoxyethylamino)azetidin-1-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N,N-diethyl-azetidine-3-carboxamide N-[3-methyl-5-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(2- fluoro-4-pyridyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[2,5-dimethyl-3-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-[6-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4- methyl-2-pyridyl]azetidine-3-carbonitrile 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]phenyl]-1,2,4-triazol-3-amine 4-(difluoromethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3-yl]- 6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N-(2-methoxyethyl)-N-methyl-azetidine-3- carboxamide N-[3-methyl-5-[3-(1,4-oxazepan-4-yl)azetidin-1-yl]phenyl]-1- pyrazin-2-yl-1,2,4-triazol-3-amine N1-[1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (3-morpholinocyclobutyl)benzene-1,3-diamine N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 5-methyl-N3-(1-methylpyrazol-3-yl)-N1-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine N-[3-ethyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1-(4- fluoro-3-methyl-phenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-isopropoxy-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine N-[3-[(8aS)-7,7-difluoro-1,3,4,6,8,8a-hexahydropyrrolo[1,2- a]pyrazin-2-yl]-5-methyl-phenyl]-1-(3,5-difluorophenyl)- 1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-pyrazol-1- ylethoxy)phenyl]-1,2,4-triazol-3-amine 1-[3-(difluoromethyl)phenyl]-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[2-fluoro-5-methyl-3-[[4-(oxetan-3- yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine 3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- morpholino-benzonitrile 1-(3-fluoro-4-methyl-phenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 4-methyl-6-morpholino-N-[1-[3-(trifluoromethyl)phenyl]- 1,2,4-triazol-3-yl]pyridin-2-amine 5-methyl-N1-oxazol-2-yl-N3-(1-phenyl-1,2,4-triazol-3- yl)benzene-1,3-diamine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (methoxymethyl)-1-piperidyl]-4-(trifluoromethyl)pyridin-2- amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[[4-(oxetan-3- yl)piperazin-1-yl]methyl]phenyl]-1,2,4-triazol-3-amine 1-(4-methoxyphenyl)-N-[3-methyl-5-(3-morpholinoazetidin-1- yl)phenyl]-1,2,4-triazol-3-amine 3-[4-(oxetan-3-yl)piperazin-1-yl]-5-[[1-(3-pyridyl)-1,2,4- triazol-3-yl]amino]benzonitrile 6-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-N-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-pyridin-2-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2- morpholinoethoxy)phenyl]-1,2,4-triazol-3-amine 3,5-dimethyl-5-[3-methyl-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]oxazolidin-2-one N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-fluoro-4-[4- (oxetan-3-yl)piperazin-1-yl]pyridin-2-amine N-[1-[3-(difluoromethyl)phenyl]-1,2,4-triazol-3-yl]-4-methyl- 6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine 4-(difluoromethyl)-N-[1-(3,4-difluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(3-methyloxetan-3-yl)piperazin-1-yl]pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-[4-(3-methoxypropyl)piperazin-1- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-oxa-8- azaspiro[4.5]decan-8-yl)phenyl]-1,2,4-triazol-3-amine 2-[3-fluoro-5-[3-[3-(3-fluoroazetidin-1-yl)-5-methyl-anilino]- 1,2,4-triazol-1-yl]anilino]ethanol 2-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-6-[4- (oxetan-3-yl)piperazin-1-yl]pyridine-4-carbonitrile N-[3-methyl-5-(4-morpholino-1-piperidyl)phenyl]-1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4-(2- methoxyethyl)-1-piperidyl]-4-methyl-pyridin-2-amine 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[3-[(2R,6R)-2,6- dimethylmorpholin-4-yl]azetidin-1-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (2-morpholinoethyl)benzene-1,3-diamine N-[1-(3-chloro-4-fluoro-phenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 4-(1,1-difluoroethyl)-N-[1-(3-fluorophenyl)-1,2,4-triazol-3- yl]-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (3-morpholinocyclobutyl)benzene-1,3-diamine N-[3-isopropoxy-2-methyl-5-[4-(oxetan-3-yl)piperaN3zin-1- yl]phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine N-[3-chloro-5-(3-morpholinoazetidin-1-yl)phenyl]-1- pyrimidin-4-yl-1,2,4-triazol-3-amine [3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-[4-(oxetan-3-yl)piperazin-1-yl]methanone 1-(3,4-difluorophenyl)-N-[3-methyl-5-(tetrahydrofuran-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (morpholinomethyl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine 4-(difluoromethyl)-6-morpholino-N-[1-[3- (trifluoromethyl)phenyl]-1,2,4-triazol-3-yl]pyridin-2-amine N-[3,5-bis(3-morpholinoazetidin-1-yl)phenyl]-1-(3,5- difluorophenyl)-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(3-methyloxetan-3-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[2-fluoro-3-methyl-5-(3- morpholinoazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-methyl-4- morpholino-pyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(3- ethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- fluoroethyl)-3-piperidyl]-5-methyl-benzene-1,3-diamine 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]ethanol 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]cyclopentanol N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol- 3-amine 3-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]propan-1-ol 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]cyclohexanol 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]piperidin-4-ol N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(2-morpholinoethyl)pyrrolidin-3-yl]benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(oxetan-3-yl)azetidin-3-yl]benzene-1,3-diamine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[2-(2,6- dimethylmorpholin-4-yl)propyl]-5-methyl-benzene-1,3- diamine cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (3-pyrrolidin-1-yltetrahydropyran-4-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(1,4-dioxan-2-ylmethyl)piperazin-1-yl]phenyl]- 1,2,4-triazol-3-amine N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-N,N-dimethyl-cyclobutanecarboxamide 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-tetrahydrofuran-2- ylmorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine N-[3-(1,4-diazabicyclo[3.2.1]octan-4-yl)-5-methyl-phenyl]-1- (3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-tetrahydrofuran-3- ylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(tetrahydrofuran-2-ylmethyl)-4-piperidyl]benzene-1,3- diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(1-methyl-3- piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[(4- ethylmorpholin-2-yl)methyl]-5-methyl-benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)pyrrolidin-3-yl]-5-methyl-benzene-1,3-diamine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(2-morpholinocyclopentyl)methyl]benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-[4-(3-methoxypropyl)-1,4- diazepan-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(1-ethyl-3- piperidyl)-5-methyl-benzene-1,3-diamine N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- (3,3,3-trifluoro-2-morpholino-propyl)benzene-1,3-diamine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-3-ethoxy-propan-2-ol 1-(3,5-difluorophenyl)-N-[3-methyl-5-(1-oxa-7- azaspiro[3.4]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-2-methyl-piperazin-1-yl]ethanol N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[(4- isobutylmorpholin-2-yl)methyl]-5-methyl-benzene-1,3- diamine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]butan-1-ol 1-cyclopentyl-4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]piperazin-2-one 1-(3,5-difluorophenyl)-N-[3-(3,7-dioxa-10- azaspiro[5.6]dodecan-10-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- phenyl-1,2,4-triazol-3-amine N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(2-pyridyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[2,3-dimethyl-5-(oxetan-3- ylmethoxy)phenyl]-1,2,4-triazol-3-amine 1-cyclobutyl-3-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]urea 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-morpholino-1- piperidyl)phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (2-morpholinocyclopentyl)benzene-1,3-diamine N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1-(3- fluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(tetrahydrofuran-2- ylmethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(oxetan-3-yl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriopiperazin-1-yl)phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(2- ethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine N1-(2-cyclopropyltetrahydropyran-4-yl)-N3-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(2S)-2- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-methyl-4- morpholino-pyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine 2-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]azetidin-3-yl]acetonitrile 2-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazin-1- yl]ethanol [3-acetoxy-2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-2-fluoro-5-methyl-phenyl]piperazin-1-yl]propyl] acetate 1-(3,5-difluorophenyl)-N-[3-methyl-5-(7-oxa-1- azaspiro[3.5]nonan-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-methyl-4-(1-methyl- 4-piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-tetrahydropyran-3-yl-piperazin-1-yl)phenyl]- 1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[2-(isopropoxymethyl)morpholin- 4-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [2-(2-methylmorpholin-4-yl)ethyl]benzene-1,3-diamine N-[3-[4-(1-deuterio-1-methyl-ethyl)piperazin-1-yl]-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)-4-piperidyl]-5-methyl-benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (1-methyl-2-morpholino-ethyl)benzene-1,3-diamine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-(1,4-dioxan- 2-ylmethyl)-5-methyl-benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-[4-[2-(dimethylamino)ethoxy]-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-1-(2-methoxyethyl)pyrrolidin-2-one 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(2,2-difluoroethyl)piperazin-1-yl]phenyl]-1,2,4- triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(tetrahydrofuran-3- ylmethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[[1- (methoxymethyl)cyclopropyl]methyl]-5-methyl-benzene-1,3- diamine 1-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]methyl]-N,N-dimethyl- cyclopentanecarboxamide N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (2-morpholinocyclohexyl)benzene-1,3-diamine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [2-(1-oxo-1,4-thiazinan-4-yl)ethyl]benzene-1,3-diamine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-2-methyl-piperazin-1-yl]-2-methyl-propan-2- ol N3-(cyclopropylmethyl)-N1-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine N1-(1-cyclobutyl-4-piperidyl)-N3-[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]-2-fluoro-5-methyl-benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-pyrrolidin-1- ylethyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-pyrrolidin-1- ylpropyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 2-[3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]methyl]azetidin-1-yl]propane-1,3-diol 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-ethyl-piperazin-1-yl)phenyl]-1,2,4-triazol-3- amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-N,N-dimethyl-piperidin-4-amine 1-(3,5-difluorophenyl)-N-[3-[4-(1,4-dioxan-2- ylmethyl)piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3- amine 1-(3,5-difluorophenyl)-N-[3-[4-(2-fluoroethoxy)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(1-morpholinocyclopropyl)methyl]benzene-1,3-diamine N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- pyrazin-2-yl-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5- methyl-N1-tetrahydrofuran-3-yl-benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-[(4-methylpiperazin- 1-yl)methyl]morpholin-4-yl]phenyl]-1,2,4-triazol-3-amine N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-fluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(1-methyl-4- piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]butan-2-ol 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]morpholin-2-yl]ethanol 2,2,2-trideuterio-1-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]ethanone N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(morpholinomethyl)propyl]benzene-1,3-diamine cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5-methyl- phenyl]piperazin-1-yl]methanone 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethoxy)-1-piperidyl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(3- ethylmorpholin-4-yl)ethyl]-2-fluoro-5-methyl-benzene-1,3- diamine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propan-1-ol 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5- dimethyl-phenoxy]-1-pyrrolidin-1-yl-ethanone N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl- phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl- phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine N3-[(4-cyclopropylmorpholin-2-yl)methyl]-N1-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-N1,5- dimethyl-N1-(oxetan-3-yl)benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2,2- dimethyltetrahydropyran-4-yl)-5-methyl-benzene-1,3-diamine 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5- dimethyl-phenoxy]azetidin-1-yl]ethanone 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2-tetrahydrofuran-2- ylmorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethyl)piperazin-1-yl]- 5-methyl-phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(5-ethyl- 2-methyl-morpholin-4-yl)ethyl]-5-methyl-benzene-1,3- diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(4-methylpiperazin- 1-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(4-ethoxy-1-piperidyl)-5-methyl- phenyl]-1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4- triazol-3-amine 6-(cyclopropylmethoxy)-N-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-4-methyl-pyridin-2-amine N-[3-(3,4,4a,5,7,7a-hexahydro-2H-furo[3,4-b]pyridin-1-yl)-5- methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(morpholinomethyl)- 1-piperidyl]phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (2-morpholinobutyl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[(3S)-3-pyrrolidin-1- ylpyrrolidin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[3-[4-[2-(diethylamino)ethyl]piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(3-methylmorpholin- 4-yl)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]piperazin-1-yl]propane-1,3-diol 3-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propan-1-ol [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-tetrahydropyran-4-yl- methanone N1-[1-(2,2-difluoroethyl)-4-piperidyl]-N3-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-benzene-1,3- diamine 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-1-pyrrolidin-1-yl-ethanone N-[3-(4-cyclobutyl-2,2,3,3,5,5,6,6-octadeuterio-piperazin-1- yl)-5-methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3- amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]propan-2-ol 1-(3,5-difluorophenyl)-N-[3-(5-ethyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)-5-methyl-phenyl]-1,2,4- triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2,2,3,3,5,5,6,6- octadeuterio-4-(3-deuteriooxetan-3-yl)piperazin-1-yl]phenyl]- 1,2,4-triazol-3-amine 1-(3,4-difluorophenyl)-N-[2-fluoro-5-methyl-3-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- tetrahydropyran-3-yloxy-pyridin-2-amine 1-(3,5-difluorophenyl)-N-[3-[4-(4-methoxybutyl)piperazin-1- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- phenyl-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[2-(2,5- dimethylmorpholin-4-yl)ethyl]-5-methyl-benzene-1,3-diamine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]benzene-1,3- diamine 1-(3,5-difluorophenyl)-N-[3-[4-(2-isopropoxyethyl)piperazin- 1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(4-methoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(2-morpholinocyclopentyl)benzene-1,3-diamine N3-[2-(cyclobutoxy)ethyl]-N1-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-pyrrolidin-1-yl-pyrrolidin-3-ol 1-(3,5-difluorophenyl)-N-[3-[4-(2-methoxyethyl)-3-methyl- piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2- (morpholinomethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (1-tetrahydropyran-4-yl-4-piperidyl)benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-tetrahydrofuran-3- yloxy-1-piperidyl)phenyl]-1,2,4-triazol-3-amine 2-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]-methyl-amino]ethanol N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5- methyl-N1-(3-methyloxetan-3-yl)benzene-1,3-diamine N-[3-[2-(diethylaminomethyl)morpholin-4-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-[2- [(dimethylamino)methyl]morpholin-4-yl]-5-methyl-phenyl]- 1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(4-isopropoxy-1-piperidyl)-5- methyl-phenyl]-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(3-pyrrolidin-1-yloxetan-3-yl)methyl]benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-fluoro-5- methyl-N1-tetrahydropyran-4-yl-benzene-1,3-diamine N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-(3-pyridyl)-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-methylmorpholin- 4-yl)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-methyl-piperazin-1-yl]-2-methyl-propan-2- ol 1-(3,5-difluorophenyl)-N-[3-[4-(4-ethylpiperazin-1-yl)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-methyl-piperazin-2-yl]ethanol 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2-(pyrrolidin-1- ylmethyl)morpholin-4-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N3-[(1- methoxycyclobutyl)methyl]-5-methyl-benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-[2-(2-methoxyethyl)morpholin-4- yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine 1-[3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]methyl]azetidin-1-yl]ethanone N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol- 3-amine 2-[2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]- 5-methyl-phenyl]piperazin-1-yl]ethoxy]ethanol N-[3-(2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl)-5-methyl- phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-oxa-7- azaspiro[2.5]octan-7-yl)phenyl]-1,2,4-triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]ethanol 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3- methylsulfonylazetidin-1-yl)phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(4-pyrrolidin-1-yl-1- piperidyl)phenyl]-1,2,4-triazol-3-amine N-[3-[4-(3-deuteriotetrahydrofuran-3-yl)piperazin-1-yl]-5- methyl-phenyl]-1-phenyl-1,2,4-triazol-3-amine 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]pyrrolidin-3-yl]pyrrolidin-3-ol cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]phenyl]piperazin-1-yl]methanone 1-(3,5-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuterio-4-tetrahydrofuran-3-yl-piperazin-1-yl)phenyl]- 1,2,4-triazol-3-amine 2-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]piperazin-1-yl]ethanol 1-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]amino]-5-methyl-phenyl]piperazin-1- yl]ethanone N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- [1-(tetrahydrofuran-3-ylmethyl)-4-piperidyl]benzene-1,3- diamine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(1-tetrahydropyran-4-yl-4-piperidyl)methyl]benzene-1,3- diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-[(1-methyl-3- piperidyl)methyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2,6- dioxaspiro[4.5]decan-9-yl)-5-methyl-benzene-1,3-diamine 5-methyl-N1-(5-methyloxazol-2-yl)-N3-(1-phenyl-1,2,4- triazol-3-yl)benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[1-(2- methoxyethyl)-3-piperidyl]-5-methyl-benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-[2- (methylsulfonylmethyl)pyrrolidin-1-yl]phenyl]-1,2,4-triazol-3- amine N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1- phenyl-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1-[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-4-piperidyl]piperidin-3-ol 1-(3,4-difluorophenyl)-N-(2-fluoro-5-methyl-3- tetrahydrofuran-3-yloxy-phenyl)-1,2,4-triazol-3-amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-2-ethyl-piperazin-1-yl]propan-2-ol 1-(3,5-difluorophenyl)-N-[3-methyl-5-(8-oxa-4- azabicyclo[4.2.0]octan-4-yl)phenyl]-1,2,4-triazol-3-amine N-[3-methyl-5-[(1-phenyl-1,2,4-triazol-3- yl)amino]phenyl]cyclopropanecarboxamide N1-(1-cyclopropylethyl)-N3-[1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-5-methyl-benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-pyrrolidin-1- ylpyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine N-(2-fluoro-5-methyl-3-tetrahydrofuran-3-yloxy-phenyl)-1-(3- fluorophenyl)-1,2,4-triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [(4-methylmorpholin-3-yl)methyl]benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-[4-(2-ethoxyethyl)-3-methyl- piperazin-1-yl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N1- (1-tetrahydrofuran-3-yl-4-piperidyl)benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-(2- methoxycyclopentyl)-5-methyl-benzene-1,3-diamine 1-(3,4-difluorophenyl)-N-[3-methyl-5-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)phenyl]-1,2,4-triazol-3-amine 4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-1-(2-methoxyethyl)piperazin-2-one 1-(3,5-difluorophenyl)-N-[3-[4-(4-methoxy-1-piperidyl)-1- piperidyl]-5-methyl-phenyl]-1,2,4-triazol-3-amine N-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4-methyl-6- (oxetan-3-ylmethoxy)pyridin-2-amine N1-(1-cyclobutyl-4-piperidyl)-N3-[1-(3,5-difluorophenyl)- 1,2,4-triazol-3-yl]-5-methyl-benzene-1,3-diamine 1-(3-fluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine 1-(3,5-difluorophenyl)-N-[2-fluoro-3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]morpholin-2-yl]methanol 1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(2-pyrrolidin-1- ylethoxy)-1-piperidyl]phenyl]-1,2,4-triazol-3-amine 1-[3-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-anilino]-3-methyl-azetidin-1-yl]-2-methoxy-ethanone 1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-methyl-azetidine-3-carbonitrile [1-[[1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]pyrrolidin-2-yl]methyl]pyrrolidin-2- yl]methanol 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]piperazin-1-yl]-3-(dimethylamino)propan-2-ol [1-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3-fluoro-azetidin-3-yl]methanol 5-deuterio-1-(3,5-difluorophenyl)-N-[3-methyl-5-[4-(oxetan-3- yl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-amine 1-(3,5-difluorophenyl)-N-[3-(2-isopropyl-2,6- diazaspiro[3.3]heptan-6-yl)-5-methyl-phenyl]-1,2,4-triazol-3- amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-5-methyl-N3- [2-(3-methylmorpholin-4-yl)ethyl]benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[3-methyl-5-(3-tetrahydrofuran-3- ylpyrrolidin-1-yl)phenyl]-1,2,4-triazol-3-amine tert-butyl 3-[[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-anilino]methyl]azetidine-1-carboxylate N-[2-fluoro-5-methyl-3-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-phenyl-1,2,4-triazol-3-amine N-[3-methyl-5-[4-[1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl]piperazin-1-yl]phenyl]-1-phenyl- 1,2,4-triazol-3-amine N-[3-[2-(cyclopropylmethoxymethyl)morpholin-4-yl]-5- methyl-phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine N-[5-deuterio-1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine N-[5-deuterio-1-(3,4-difluorophenyl)-1,2,4-triazol-3-yl]-6-[4- (oxetan-3-yl)piperazin-1-yl]-4-(trifluoromethyl)pyridin-2- amine N-[5-deuterio-1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-4- (difluoromethyl)-6-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2- amine 5-deuterio-N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1- yl]phenyl]-1-[3-(trifluoromethyl)phenyl]-1,2,4-triazol-3-amine 2-[1-[3-[[5-deuterio-1-(3,5-difluorophenyl)-1,2,4-triazol-3- yl]amino]-5-methyl-phenyl]azetidin-3-yl]propan-2-ol 2-cyclopropyl-N-[5-deuterio-1-(3,5-difluorophenyl)-1,2,4- triazol-3-yl]-6-morpholino-pyridin-4-amine 2-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5- dimethyl-phenoxy]-1-morpholino-ethanone N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3,4-difluorophenyl)-1,2,4-triazol- 3-amine cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[[1-(3,4-difluorophenyl)-1,2,4-triazol-3- yl]amino]phenyl]piperazin-1-yl]methanone 1-(3,5-difluorophenyl)-N-[3-methyl-5-[3-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine 1-(3,4-difluorophenyl)-N-[3-methyl-5-[3-(2,2,3,3,5,5,6,6- octadeuteriomorpholin-4-yl)azetidin-1-yl]phenyl]-1,2,4- triazol-3-amine N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3,4-difluorophenyl)-1,2,4-triazol- 3-amine cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3,4- difluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-(3-fluorophenyl)-1,2,4-triazol-3- amine N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-(3-fluorophenyl)-1,2,4-triazol-3- amine cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3-[[1-(3- fluorophenyl)-1,2,4-triazol-3-yl]amino]-5- (trifluoromethyl)phenyl]piperazin-1-yl]methanone cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[[1-(3-fluorophenyl)-1,2,4-triazol-3- yl]amino]phenyl]piperazin-1-yl]methanone N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (trifluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine N-[3-(2,2,3,3,4,4,5,5,6,6-decadeuterio-1-piperidyl)-5- (difluoromethyl)phenyl]-1-pyrazin-2-yl-1,2,4-triazol-3-amine cyclopropyl-[2,2,3,3,5,5,6,6-octadeuterio-4-[3- (difluoromethyl)-5-[(1-pyrazin-2-yl-1,2,4-triazol-3- yl)amino]phenyl]piperazin-1-yl]methanone N-[3-methyl-5-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1- (2,3,4,5,6-pentadeuteriophenyl)-1,2,4-triazol-3-amine N3-benzyl-N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2- fluoro-5-methyl-benzene-1,3-diamine N-[3-[4-(3-deuteriooxetan-3-yl)piperazin-1-yl]-5-methyl- phenyl]-1-(3,5-difluorophenyl)-1,2,4-triazol-3-amine N-[3-methyl-5-(2,2,3,3,5,5,6,6-octadeuterio-4-methyl- piperazin-1-yl)phenyl]-1-phenyl-1,2,4-triazol-3-amine [4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]piperazin-1-yl]-tetrahydropyran-4-yl- methanone 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[3-methyl-4- (1-methyl-4-piperidyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3- amine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-N1-[2-(2- ethylmorpholin-4-yl)ethyl]-2-fluoro-5-methyl-benzene-1,3- diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-[1-(tetrahydrofuran-3-ylmethyl)-4- piperidyl]benzene-1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-[1-(tetrahydrofuran-2-ylmethyl)-4- piperidyl]benzene-1,3-diamine 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[3-(4- methylpiperazin-1-yl)azetidin-1-yl]phenyl]-1,2,4-triazol-3- amine N3-[(4-cyclopropylmorpholin-2-yl)methyl]-N1-[1-(3,5- difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5-methyl-benzene- 1,3-diamine N3-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N1-(1-methyl-2-morpholino-ethyl)benzene-1,3- diamine 1-(3,5-difluorophenyl)-N-[2-fluoro-3-[2- (isopropoxymethyl)morpholin-4-yl]-5-methyl-phenyl]-1,2,4- triazol-3-amine N1-[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]-2-fluoro-5- methyl-N3-[(1-morpholinocyclopropyl)methyl]benzene-1,3- diamine 1-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-(3- tetrahydrofuran-3-ylazetidin-1-yl)phenyl]-1,2,4-triazol-3- amine 1-[4-[3-[[1-(3,5-difluorophenyl)-1,2,4-triazol-3-yl]amino]-2- fluoro-5-methyl-phenyl]-2-methyl-piperazin-1-yl]-2-methyl- propan-2-ol


67. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of claims 1-66, or 87, or a pharmaceutically acceptable salt thereof.
 68. A method of treating a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy, and a leukodystrophy, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition thereof of any of claims 1-67, or 87, or a pharmaceutically acceptable salt thereof.
 69. The method of claim 68, wherein the disease or disorder is a demyelinating disease selected from multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica, optic neuritis, and transverse myelitis.
 70. The method of claim 69, wherein the demyelinating disease is multiple sclerosis.
 71. The method of claim 70, wherein the type of multiple sclerosis is primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis.
 72. The method of claim 68, wherein the disease or disorder is a leukodystrophy selected from the group consisting of adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease, Globoid cell Leucodystrophy (Krabbe's disease), cerebrotendineous xanthomatosis, hereditary CNS demyelinating disease, metachromatic leukodystrophy, Canavan disease, adrenoleukodystrophy, Refsum disease, and xenobefantosis.
 73. The method of claim 68, wherein the disease or disorder is a leukoencephalopathy selected from progressive multifocal leukoencephalopathy.
 74. The method of claim 68, wherein the disease or disorder is a nerve injury disease or disorder selected from spinal cord injury, cerebral palsey, periventricular leukomalacia and Wallerian degeneration.
 75. A method of promoting remyelination of demyelinated axons comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition thereof of any of claims 1-67, or claim 87, or a pharmaceutically acceptable salt thereof.
 76. A method of differentiating endogenous oligodendrocyte precursor cells, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition thereof of any of claims 1-67, or 87, or a pharmaceutically acceptable salt thereof.
 77. A method of treating, preventing, or reducing the severity of one or more symptoms of multiple sclerosis or another neurodegenerative disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition thereof of any of claims 1-67, or 87, or a pharmaceutically acceptable salt thereof.
 78. The method of claim 77, wherein the one or more symptoms of multiple sclerosis or another neurodegernative disease is selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor-sphincter dyssynergia, erectile dysfunction or anorgasmy.
 79. The method of claim 68, wherein the disease or disorder is selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, essential tremor or osmotic hyponatremia.
 80. A compound or pharmaceutical composition thereof of any of claims 1-67, or 87, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy, a leukodystrophy, or multiple sclerosis; or for the promotion of remyelination of demyelinated axons; or for the differentiation of endogenous oligodendrocyte precursor cells.
 81. A compound or pharmaceutical composition thereof of any of claims 1-67, or 87, or a pharmaceutically acceptable salt thereof, for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy, a leukodystrophy, or multiple sclerosis; or for use in promoting remyelination of demyelinated axons; or for use in differentiating endogenous oligodendrocyte precursor cells.
 82. A kit comprising the compound of any one of claims 1 to 66, or 87 or the pharmaceutical composition of claim 67, and instructions for use thereof.
 83. The kit of claim 82, further comprising one or more additional therapeutic agent(s).
 84. The kit of claim 82 or 83, wherein the compound of any one of claims 1 to 66, or 87 or the pharmaceutical composition of claim 67 and the one or more additional therapeutic agent(s) are in separate containers.
 85. The kit of claim 82 or 83 wherein the compound of any one of claims 1 to 66, or 87 or the pharmaceutical composition of claim 67 and the one or more additional therapeutic agent(s) are in the same container.
 86. The kit of claim 84 or 85, wherein the container is a bottle, vial, or blister pack, or combinations thereof.
 87. A compound of formula (I′), or a pharmaceutically acceptable salt thereof,

wherein: X¹ is CH or N; X² is CR^(X2) or N; X³ is CR³ or N; where R³ and R^(X2) are each independently selected from the group consisting of hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, and cyano; provided that X¹, X², and X³ are not simultaneously N, X² and X³ are not simultaneously N, and X¹ and X³ are not simultaneously N; L¹ is a bond, —O—, —NR⁵—, —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, —C(O)—, —NR⁵C(O)—, —OC(O)—, —NR⁵C(O)NR⁵—, —NR⁵C(O)O—, —NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O—, wherein each R⁵ is independently hydrogen or C₁₋₄alkyl, and the C₁₋₄alkylene of —NR⁵—C₁₋₄alkylene-, —O—C₁₋₄alkylene-, —C₁₋₄alkylene-, —NR⁵—C₁₋₄alkylene-C(O)—, —O—C₁₋₄alkylene-C(O)—, —C₁₋₄alkylene-C(O)—, —NR⁵C(O)—C₁₋₄alkylene-, —OC(O)—C₁₋₄alkylene-, —NR⁵C(O)NR⁵—C₁₋₄alkylene-, —NR⁵C(O)O—C₁₋₄alkylene-, or —NR⁵—C₁₋₄alkylene-O— is optionally substituted with 1-6 halogens; R¹ is -G¹-L²-R⁶, -G¹-L²-R⁷, G², G³, G⁴, G⁵, G⁶, G⁷, or -≡-G; G¹ is i) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; or ii) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; L² is a bond, a —C₁₋₆alkylene-, —C(O)—, —O—, or —NR^(5′)—, wherein the —C₁₋₆alkylene- is optionally substituted with 1-6 halogens and 1-2 C₁alkylene units of the —C₁₋₆alkylene- are optionally replaced with —C(O)—, —O—, or —NR⁵—, wherein each R⁵ is independently hydrogen or C₁₋₄alkyl; R⁶ is a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, —CH₂S(O)₂phenyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; b) a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; c) a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L², the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; or d) a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; R⁷ is a) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, oxo, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; or b) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, —C(O)OC₁₋₄alkyl, —C(O)OH, —OC₁₋₄alkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, and —C₁₋₆alkylene-OH; G² is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C₁₋₃alkylene bridge between two non-adjacent ring atoms, G² being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C₁₋₆alkylene-cyano, —C(O)C₁₋₄alkyl, —C(O)—C₁₋₆alkylene-OC₁₋₄alkyl, —C(O)—C₁₋₆alkylene-OH, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₆alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene-NH₂, —C₁₋₆alkylene-NH(C₁₋₄alkyl), —C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —O—C₁₋₆alkylene-NH₂, —O—C₁₋₆alkylene-NH(C₁₋₄alkyl), —O—C₁₋₆alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —O—C₁₋₆alkylene-OC₁₋₄alkyl, —O—C₁₋₆alkylene-OH, —C₁₋₄alkylene-O—C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-O—C₁₋₄alkylene-OH, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), —S(O)₁₋₂C₁₋₄alkyl, —C₁₋₆alkylene-S(O)₁₋₂C₁₋₄alkyl, and a —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl, —OC(O)C₁₋₄alkyl, —OC₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); G³ is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L¹, the second ring being a C₃₋₈cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G³ is optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; G⁴ is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁴ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; G⁵ is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); G⁶ is a monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G⁶ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); G⁷ is aryl optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C₁₋₄alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)OC₁₋₄alkyl, —C(O)OC₁₋₄haloalkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —C(O)NH(—C₁₋₆alkylene-OH), —C(O)N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —NH(—C₁₋₆alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OC₁₋₄alkyl), —NH(—C₁₋₆alkylene-OH), —N(C₁₋₄alkyl)(-C₁₋₆alkylene-OH), —C(O)C₁₋₄haloalkyl, —OC₁₋₄alkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₆alkylene-OH, —C₁₋₆alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C₁₋₄alkyl, —C₁₋₄alkylene-C(O)OC₁₋₄alkyl, —C₁₋₄alkylene-C(O)OH, —NHC(O)(C₁₋₄alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)(C₁₋₄alkyl); R² is C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C(O)C₁₋₄alkyl, —C(O)OC₁₋₄alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-OH, or G¹⁰, G¹⁰ being a C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen and optionally containing 1 double bond, G¹⁰ being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl, and G²⁰, G²⁰ being a C₃₋₆cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G²⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, halogen, hydroxyl, and oxo; and R⁴ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R⁴ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —S(O)₂C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —SC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —OC₁₋₄alkyl, —OC₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, —C₁₋₄alkylene-N(C₁₋₄alkyl)(C₁₋₄alkyl), —NH(C₁₋₄alkylene-OC₁₋₄alkyl), —NH(C₁₋₄alkylene-OH), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OC₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkylene-OH), —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), C₃₋₆cycloalkyl, C₅₋₆cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C₃₋₆cycloalkyl, the C₅₋₆cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, —C₁₋₄alkylene-OC₁₋₄alkyl, and —C₁₋₄alkylene-OH. 